Background
Endocrine therapy has played a crucial role in managing hormone receptor–positive breast cancer for >5 decades. However, disease progression often exposes the limitations of endocrine monotherapy, especially concerning tumor resistance.1 This challenge has led to the integration of CDK4/6 inhibitors (ie, palbociclib, ribociclib, and abemaciclib) into treatment. These inhibitors, commonly used alongside endocrine therapies, have gained attraction over the past 8 years. Randomized controlled trials (RCTs) have demonstrated their efficacy, significantly improving survival and clinical outcomes compared with endocrine monotherapy.2–11 For example, the phase II PALOMA-1 trial showed that adding palbociclib to letrozole nearly doubled the median progression-free survival in patients with estrogen receptor–positive and HER2-negative (ER+/HER2−) advanced breast cancer (20.2 vs 10.2 months).11
Despite their survival benefits, the class of CDK4/6 inhibitors has raised concerns about cardiotoxicity.12 An observational study from the OneFlorida Data Trust reported a cardiotoxicity incidence of 16.8% among patients without prior cardiovascular (CV) disease who were treated with at least one type of CDK4/6 inhibitor, with a mortality rate of 17.2% among these patients.13 Mortality rates were notably higher in patients who developed complications such as atrial fibrillation/atrial flutter or heart failure posttreatment.14 Additionally, data from the FDA Adverse Events Reporting System (FAERS) for 2018–2019 showed 805 cardiac adverse events among 27,079 patients treated with CDK4/6 inhibitors, with atrial fibrillation, myocardial infarction, cardiac failure, and pericardial effusion being the most commonly reported.15 In addition to the effect of the class of CDK4/6 inhibitors, further research has compared the CV risk of different types of CDK4/6 inhibitors. A recent meta-analysis of RCTs suggested that abemaciclib, combined with endocrine therapy, may pose a lower risk of major adverse cardiovascular events (MACE) in the treatment of advanced breast cancer, whereas palbociclib may be associated with a reduced risk of hypertension.16 Furthermore, a phase III RCT identified potential QT prolongation with CDK4/6 inhibitors, indicating that ribociclib carries a higher CV risk than palbociclib.17,18 Despite existing data, a gap remains in real-world evidence comparing the CV safety of the 3 CDK4/6 inhibitors. Therefore, conducting comprehensive real-world studies is critical to enhancing treatment strategies that improve both CV safety and overall survival in patients with advanced breast cancer.
In addition to cardiotoxicity, the increased health care costs associated with CV events raises concerns. Adding palbociclib, ribociclib, or abemaciclib to letrozole significantly increases cost by $799,178, $788,168, and $741,102 respectively, compared with letrozole alone.19 The potential for CDK4/6 inhibitors to elevate the risk of CV adverse events may worsen clinical outcomes, further escalating costs. A study of 50,010 patients with breast cancer in Taiwan found that CV adverse events related to left heart failure resulted in an additional cost of $3,585 per patient.20 Economic analyses consistently indicate that adding CDK4/6 inhibitors to endocrine therapy is not cost-effective compared with endocrine therapy alone.21 However, studies assessing the incremental costs specifically associated with CV adverse events following CDK4/6 inhibitor use are lacking.
Bringing these findings together, the primary objective of our study was to compare the incidence of hypertension and MACE across individual CDK4/6 inhibitors in breast cancer treatment. The secondary objective was to estimate the additional health care costs for patients who developed hypertension and MACE after initiating CDK4/6 inhibitors, compared with those who did not experience these adverse events.
Methods
Data Source
The Merative MarketScan Research Database is a comprehensive source of deidentified medical and pharmacy claims data. Our study utilized MarketScan commercial claims and encounters data, which cover nearly 30 million employer-sponsored employees, early retirees, and their dependents annually. This data includes demographics, inpatient and outpatient services, comorbidities, dispensed prescription, service costs, and health care plan characteristics. The Institutional Review Board at The University of Texas at Austin determined that this study does not involve human subjects and is exempt from review.
Study Design
We conducted a retrospective cohort study using the 2017–2021 MarketScan Research Database. The index date was defined as the initiation date of any CDK4/6 inhibitor following the earliest breast cancer diagnosis. The index identification period spanned from January 1, 2018, to December 31, 2021. The preindex period was defined as the 12 months prior to the index date, during which preexisting comorbidities were assessed. The postindex period was defined from the date of initiation of CDK4/6 inhibitors until censoring, which occurred at the incidence of hypertension or MACE, death, or the end of the study period.
Study Population
We included women with breast cancer who initiated CDK4/6 inhibitors. Patients met the inclusion criteria if they: (1) had a breast cancer diagnosis (ICD-10-CM: C50.xx); (2) initiated a CDK4/6 inhibitor (palbociclib, ribociclib, or abemaciclib) after their earliest breast cancer diagnosis; (3) were aged >18 years; (4) were female; and (5) had at least 12 months of continuous eligibility prior to the index date. Two cohorts were defined: the hypertension cohort and the MACE cohort.
For the first objective of measuring the incidence of hypertension and MACE, the hypertension cohort included patients without hypertension in the 12 months prior to the index date, and the MACE cohort included those without hypertension or MACE during that period. For the second objective of estimating costs, we matched CDK4/6 inhibitor users who experienced hypertension with those who did not within the hypertension cohort and those who experienced MACE with those who did not within the MACE cohort (Figure 1).
Flowchart of patients with breast cancer initiating CDK4/6 inhibitors.
Abbreviation: MACE, major adverse cardiac events.
Citation: Journal of the National Comprehensive Cancer Network 23, 5; 10.6004/jnccn.2025.7001
Measures
CDK4/6 inhibitors were categorized as palbociclib, ribociclib, or abemaciclib and identified using NDC codes (Supplementary Table S1, available online in the supplementary materials). The incidence of hypertension or MACE was used as a time-to-event outcome variable, defining the time from CDK4/6 inhibitor initiation to the earliest incidence of hypertension or MACE, and identified using ICD-10-CM codes (Supplementary Table S2). MACE included heart failure, cardiomyopathy, myocardial infraction, angina, arrythmias, and stroke. Health care costs were assessed based on hospitalization, outpatient visits, emergency department (ED) visits, and prescriptions during the follow-up period, and reported per-patient-per-month (PPPM). Costs were calculated based on gross payments to providers per claim.
Baseline characteristics at breast cancer diagnosis included age, region, and health care plan type. We also included breast cancer treatment–related information during the preindex period, such as receipt of chemotherapy, endocrine therapy, targeted therapy, surgery, and radiation. Additionally, comorbid hyperlipidemia, comorbid diabetes, and metastasis status were assessed. For descriptive purposes, we measured the duration of CDK4/6 inhibitor use by calculating the number of days between the first and last prescription in the postindex period.
Statistical Analyses
Descriptive statistics were used to compare demographics and clinical characteristics between CDK4/6 inhibitor groups and between hypertension and MACE groups, with t tests or paired t tests applied for continuous variables and Rao-Scott chi-square tests or McNemar tests used for categorical variables.
A Cox proportional hazards model assessed the risk of hypertension and MACE during the follow-up period, after controlling for covariates. Hazard ratios (HRs) with 95% confidence intervals were reported.
Patients with and without hypertension or MACE were matched based on covariates using propensity scores to balance demographics and clinical characteristics. Propensity scores were generated via multivariate logistic regression, and nearest-neighbor matching was performed using the greedy algorithm. To compare overall health care, outpatient, and prescription costs between groups while controlling for covariates, a generalized linear model (GLM) with a gamma distribution and log-link function was used. For cost categories with many zero-expenditure values, such as inpatient and ED costs, a 2-part or zero-inflated model with a Poisson distribution was applied. The 2-part model consisted of a logistic regression to estimate the probability of incurring any health care cost (zero vs nonzero) and a GLM with a gamma distribution and log-link function to estimate costs for patients with positive expenditures, accounting for the right-skewed distribution. Incremental costs were calculated by subtracting the costs of patients without hypertension or MACE from those with these conditions, adjusting for covariates. Health care costs were adjusted to 2021 US dollars using the medical component of the Consumer Price Index. All analyses were conducted using SAS version 9.4 (SAS Institute Inc.) and Stata, version 17 (StatCorp LLC), with 2-tailed tests and a significance level set at P<.05.
Results
Incidence of Hypertension and MACE After CDK4/6 Inhibitor Initiation
Patient Characteristics
A total of 2,780 patients were included in the hypertension cohort and 2,043 in the MACE cohort. Table 1 and Supplementary Table S3 summarize the baseline demographics of patients with no prior hypertension who received palbociclib (n=2,048; 73.6%), ribociclib (n=174; 6.3%), or abemaciclib (n=558; 20.1%). Metastasis sites differed significantly among the 2 treatment groups, whereas other baseline characteristics, such as medical history, type of health care plan, and age, showed no statistically significant differences. Supplementary Table S4 presents the baseline characteristics of patients without MACE or hypertension who received palbociclib (n=1,558; 76.2%), ribociclib (n=115; 5.6%), or abemaciclib (n=370; 18.2%) on the index date. Baseline chemotherapy treatments varied significantly across groups. Additionally, a significantly higher proportion of patients in the palbociclib group received endocrine therapy compared with those in the abemaciclib or ribociclib groups. No statistically significant differences were found in geographic distribution or health plan types across the 3 groups.
Patient Characteristics: Hypertension Cohort (N=2,780)
| Characteristic | Palbociclib n (%) |
Ribociclib n (%) |
Abemaciclib n (%) |
P Valuea |
|---|---|---|---|---|
| Total | 2,048 (100.0) | 174 (100.0) | 558 (100.0) | |
| Age, mean [SD], y | 56.4 [10.6] | 51.8 [10.6] | 53.4 [11.2] | <.001 |
| Age group | <.001 | |||
| 18–34 y | 42 (2.1) | <11 (NA) | 25 (4.5) | |
| 35–44 y | 232 (11.3) | 40 (23.0) | 104 (18.6) | |
| 45–54 y | 575 (28.1) | 62 (35.6) | 164 (29.4) | |
| 55–64 y | 858 (41.9) | 49 (28.2) | 214 (38.4) | |
| 65–74 y | 237 (11.6) | 12 (6.9) | 28 (5.0) | |
| ≥75 y | 104 (5.1) | <11 (NA) | 23 (4.1) | |
| Region | .074 | |||
| Northeast | 454 (22.2) | 24 (13.8) | 115 (20.6) | |
| North Central | 469 (22.9) | 46 (26.4) | 120 (21.5) | |
| South | 778 (38.0) | 61 (35.1) | 224 (40.1) | |
| West | 345 (16.9) | 43 (24.7) | 99 (17.7) | |
| Health plan type | .074 | |||
| Comprehensive | 98 (4.8) | <11 (NA) | 28 (5.0) | |
| EPO | 21 (1.0) | <11 (NA) | <11 (NA) | |
| HMO | 224 (10.9) | 19 (10.9) | 66 (11.8) | |
| POS | 113 (5.5) | 13 (7.5) | 51 (9.1) | |
| PPO | 1,078 (52.6) | 94 (54.0) | 266 (47.7) | |
| POS with capitation | 14 (0.7) | <11 (NA) | <11 (NA) | |
| CDHP | 239 (11.7) | 16 (9.2) | 52 (9.3) | |
| HDHP | 213 (10.4) | 19 (10.9) | 79 (14.2) | |
| CCI score, mean [SD] | 8.4 [1.7] | 8.4 [1.7] | 8.2 [2.0] | .281 |
| Major cardiovascular disease | ||||
| Atrial fibrillation | 34 (1.7) | <11 (NA) | <11 (NA) | .557 |
| Coronary artery disease | 65 (3.2) | <11 (NA) | 17 (3.1) | .813 |
| Cardiomegaly | 50 (2.4) | <11 (NA) | 13 (2.3) | .984 |
| Cardiomyopathy | 32 (1.6) | <11 (NA) | <11 (NA) | .530 |
| Heart failure | 42 (2.1) | <11 (NA) | <11 (NA) | .278 |
| Peripheral artery disease | 65 (3.2) | <11 (NA) | 15 (2.7) | .710 |
| Stroke | 44 (2.2) | <11 (NA) | 16 (2.9) | .221 |
| Hyperlipidemia | 460 (22.5) | 32 (18.4) | 111 (19.9) | .235 |
| Diabetes | 154 (7.5) | 11 (6.3) | 39 (7.0) | .793 |
| Metastasis | ||||
| Lung | 574 (28.0) | 55 (31.6) | 125 (22.4) | .012 |
| Liver | 781 (38.1) | 64 (36.8) | 182 (32.6) | .057 |
| Brain | 341 (16.7) | 24 (13.8) | 107 (19.2) | .190 |
| Bone | 1,682 (82.1) | 143 (82.2) | 360 (64.5) | <.001 |
| Bone only | 544 (26.6) | 48 (27.6) | 87 (15.6) | <.001 |
| Visceral | 1,150 (56.2) | 93 (53.5) | 264 (47.3) | .001 |
| Chemotherapy | ||||
| Capecitabine | 64 (3.1) | <11 (NA) | 48 (8.6) | .948 |
| Doxorubicin | 85 (4.2) | 12 (6.9) | 106 (19.0) | .931 |
| Eribulin | 12 (0.6) | <11 (NA) | 22 (3.9) | .989 |
| Gemcitabine | 22 (1.1) | <11 (NA) | 23 (4.1) | .977 |
| Paclitaxel | 157 (7.7) | 17 (9.8) | 135 (24.2) | .902 |
| Vinorelbine | 11 (0.5) | <11 (NA) | <11 (NA) | .989 |
| Targeted mutation therapy | ||||
| Alpelisib | <11 (NA) | <11 (NA) | <11 (NA) | 1.000 |
| Everolimus | 24 (1.2) | <11 (NA) | 23 (4.1) | .989 |
| Olaparib | <11 (NA) | <11 (NA) | <11 (NA) | .989 |
| Talazoparib | <11 (NA) | <11 (NA) | <11 (NA) | 1.000 |
| Procedures | ||||
| Breast-conserving surgery | 81 (4.0) | <11 (NA) | 46 (8.2) | <.001 |
| Mastectomy | 114 (5.6) | 12 (6.9) | 85 (15.2) | <.001 |
| Radiation | 470 (23.0) | 44 (25.3) | 211 (37.8) | <.001 |
| Endocrine therapy before CDK4/6 initiation | ||||
| Anastrozole | 411 (20.1) | 24 (13.8) | 143 (25.6) | .862 |
| Exemestane | 185 (9.0) | <11 (NA) | 65 (11.7) | .954 |
| Fulvestrant | 509 (24.9) | 27 (15.5) | 130 (23.3) | .845 |
| Letrozole | 1,014 (49.5) | 76 (43.7) | 191 (34.2) | .563 |
| Tamoxifen | 310 (15.1) | 34 (19.5) | 97 (17.4) | .805 |
| Endocrine therapy after CDK4/6 initiation | ||||
| Anastrozole | 251 (12.3) | 16 (9.2) | 96 (17.2) | .003 |
| Exemestane | 285 (13.9) | 16 (9.2) | 57 (10.2) | .022 |
| Fulvestrant | 1,001 (48.9) | 56 (32.2) | 232 (41.6) | <.001 |
| Letrozole | 1,024 (50.0) | 117 (67.2) | 156 (28.0) | <.001 |
| Tamoxifen | 84 (4.1) | 12 (6.9) | 22 (3.9) | .198 |
| Time between first and last prescription of each CDK4/6 inhibitorb | ||||
| Palbociclib | ||||
| Patients, n | 2,048 (100.0) | 14 (8.0) | 38 (6.8) | |
| Mean [SD], d | 353.3 [353.4] | 378.8 [256.2] | 215.3 [237.8] | .054 |
| Ribociclib | ||||
| Patients, n | 17 (0.8) | 174 (100.0) | <11 (NA) | |
| Mean [SD], d | 109.4 [132.8] | 288.0 [316.3] | 152.1 [367.2] | .043 |
| Abemaciclib | ||||
| Patients, n | 178 (8.7) | <11 (NA) | 558 (100.0) | |
| Mean [SD], d | 166.6 [213.7] | 63.3 [62.2] | 199.8 [238.2] | .075 |
To protect patient confidentiality, exact patient counts are not reported for cells containing <11 individuals.
Abbreviations: CCI, Charlson comorbidity index; CDHP, consumer directed health plan; EPO, exclusive provider organization; HDHP, high deductible health plan; HMO, health maintenance organization; NA, not applicable; POS, point-of-service; PPO, preferred provider organization.
Chi-square tests were used for categorical variables, and ANOVA was used for continuous variables.
Patients may have received multiple CDK4/6 inhibitors during the postindex period.
Incidence of Hypertension and MACE
Supplementary Tables S5 and S6 present the incidence of hypertension and MACE per 100 person-years following CDK4/6 inhibitor initiation. The estimated hypertension incidence per 100 person-years was 12.8 (95% CI, 8.9–18.3) for ribociclib, 11.8 (95% CI, 9.2–15.2) for abemaciclib, and 10.4 (95% CI, 9.4–11.6) for palbociclib. Similarly, the estimated MACE incidence per 100 person-years was 23.0 (95% CI, 16.7–31.5) for ribociclib, 25.1 (95% CI, 20.5–30.7) for abemaciclib, and 18.3 (95% CI, 16.7–20.0) for palbociclib.
Figures 2 and 3, along with Supplementary Tables S7 and S8, present the risks of hypertension and MACE following CDK4/6 inhibitor initiation. Compared with ribociclib, neither abemaciclib (HR, 0.791; 95% CI, 0.507–1.232) nor palbociclib (HR, 0.723; 95% CI, 0.493–1.060) showed a statistically significant difference in hypertension risk, although both had lower HR point estimates. For MACE, palbociclib was associated with a statistically significant lower risk (HR, 0.636; 95% CI, 0.454–0.892), whereas abemaciclib showed a similar trend without statistical significance (HR, 0.795; 95% CI, 0.540–1.169).
Hazard ratios for time to onset of hypertension and MACE by type of CDK4/6 inhibitor. Bold indicates statistically significant P value.
Abbreviations: HR, hazard ratio; MACE, major adverse cardiac events.
aEstimates were generated using a Cox proportional hazards model without covariates.
bEstimates were generated using a Cox proportional hazards model that controlled for age; region; health plan type; history of cardiovascular disease; metastasis; hyperlipidemia; diabetes; different treatment types, such as chemotherapy, endocrine therapy, targeted mutation therapy, and procedures, such as breast-conserving surgery, mastectomy, and radiation therapy.
Citation: Journal of the National Comprehensive Cancer Network 23, 5; 10.6004/jnccn.2025.7001
Kaplan-Meier plot for time to onset of HTN and MACE by type of CDK4/6 inhibitor.
Abbreviations: HTN, hypertension; MACE, major adverse cardiac events.
Citation: Journal of the National Comprehensive Cancer Network 23, 5; 10.6004/jnccn.2025.7001
Costs by Hypertension and MACE After CDK4/6 Inhibitor Initiation
Patient Characteristics
Supplementary Tables S9 and S10 present the baseline characteristics of patients who developed hypertension or MACE, respectively, compared with those who did not, after balancing for covariates.
Health Care Costs by Hypertension and MACE
Before any adjustments, significant differences in health care costs were observed between patients with and without hypertension (Supplementary Table S11) and between those with and without MACE (Supplementary Table S12).
Table 2 presents the adjusted differences in costs between patients who developed hypertension or MACE and those who did not, controlling for covariates. Total health care costs were significantly higher for patients with hypertension (incremental cost, $2,964 PPPM; P=.001), including inpatient (incremental cost, $662 PPPM; P=.014), ED (incremental cost, $195 PPPM; P<.0001), and outpatient care (incremental cost,$1,398 PPPM; P=.005). However, prescription costs were lower in patients with hypertension ($9,533) compared with those without ($11,114; P<.0001). For patients with MACE, costs were substantially higher across multiple categories, including total health care (incremental cost, $4,010 PPPM; P<.0001), inpatient (incremental cost, $970 PPPM; P=.013), ED (incremental cost, $280 PPPM; P<.0001), and outpatient costs (incremental cost, $3,149 PPPM; P<.0001). Similar to hypertension, prescription costs were lower for patients with MACE ($8,379 PPPM) compared with those without ($11,806 PPPM; P<.0001).
Health Care Costs PPPM by Hypertension or MACE Incidence After CDK4/6 Inhibitor Initiation
| Hypertension | No Hypertension | Increment Cost | |||||
|---|---|---|---|---|---|---|---|
| Mean | (95% CI) | Mean | (95% CI) | ΔCosts | (95% CI) | P Value | |
| Total cost | $21,475 | ($20,199–$22,752) | $18,512 | ($17,402–$19,622) | $2,964 | ($1,272–$4,655) | .001 |
| Inpatient cost | $902 | ($357–$1,447) | $240 | ($26–$454) | $662 | ($133–$1,191) | .014 |
| ED cost | $367 | ($288–$446) | $172 | ($126–$218) | $195 | ($105–$285) | <.0001 |
| Outpatient cost | $7,640 | ($6,865–$8,415) | $6,243 | ($5,596–$6,889) | $1,398 | ($420–$2,376) | .005 |
| Prescription cost | $9,533 | ($9,104–$9,962) | $11,114 | ($10,609–$11,618) | ($1,581) | ([$2,245]–[$917]) | <.0001 |
| MACE | No MACE | Increment Cost | |||||
| Mean | (95% CI) | Mean | (95% CI) | ΔCosts | (95% CI) | P Value | |
| Total cost | $22,887 | ($21,673–$24,101) | $18,877 | ($17,864–$19,889) | $4,010 | ($2,431–$5,589) | <.0001 |
| Inpatient cost | $1,208 | ($288–$2,128) | $238 | ($3–$473) | $970 | ($202–$1,738) | .013 |
| ED cost | $415 | ($350–$480) | $135 | ($101–$169) | $280 | ($209–$351) | <.0001 |
| Outpatient cost | $9,087 | ($8,377–$9,797) | $5,938 | ($5,469–$6,408) | $3,149 | ($2,310–$3,989) | <.0001 |
| Prescription cost | $8,379 | ($8,010–$8,747) | $11,806 | ($11,288–$12,323) | ($3,427) | ([$4,063]–[$2,791]) | <.0001 |
All costs were adjusted to 2021 USD values.
Abbreviations: ED, emergency department; MACE, major adverse cardiac events; PPPM, per patient per month.
Discussion
Combining CDK4/6 inhibitors with endocrine therapy has significantly improved survival rates for patients with breast cancer.22–24 However, the CV adverse events associated with CDK4/6 inhibitors pose a significant challenge for patients and health care systems.25,26 Although prior studies have documented these adverse events, few observational studies have compared the incidence of CV events among individual CDK4/6 inhibitors.13–15 Our study aimed to address this gap by comparing the incidence of hypertension and MACE following the initiation of each CDK4/6 inhibitor. Additionally, we evaluated the incremental costs associated with hypertension and MACE in patients receiving these inhibitors, providing the first evidence of their significant impact on health care costs.
Our results showed that both palbociclib and abemaciclib were associated with a lower risk of hypertension compared with ribociclib, though neither was statistically significant. For MACE, palbociclib demonstrated a significantly lower risk than ribociclib, whereas abemaciclib also showed a lower risk but not statistically significant. Patients who developed hypertension or MACE incurred significantly higher health care costs, underscoring the financial burden of these adverse events.
Our findings are consistent with previous studies demonstrating a lower risk of hypertension and CV events with palbociclib and abemaciclib compared with ribociclib. In our previously published network meta-analysis (NMA), which summarized data from 9 RCTs involving 5,219 patients with breast cancer, both palbociclib and abemaciclib were associated with a lower incidence of MACE and hypertension compared with ribociclib.16 Furthermore, an analysis of the FAERS found that ribociclib, but not palbociclib or abemaciclib, was significantly associated with increased odds of atrial fibrillation, further highlighting the variability in cardiotoxic profiles of these agents.27
The use of CDK4/6 inhibitors generally increases the risk of developing CV diseases through various mechanisms, including left ventricular hypertrophy, hypertension, thromboembolism, and vascular inflammation.17,28,29 However, ribociclib’s association with QTc prolongation likely contributes to its higher CV risk.30,31 Another meta-analysis showed that ribociclib was associated with a higher absolute risk of QTc prolongation compared with palbociclib.32 This finding aligns with the MONALEESA-7 trial, which reported a significant incidence of QTc prolongation in patients treated with ribociclib.7 Additionally, gene expression studies have shown that ribociclib can alter potassium and sodium channels, further highlighting its distinct cardiotoxic profile.33–35
Interestingly, despite the documented risk of QTc prolongation with ribociclib, our results did not show a statistically significant difference in the risk of MACE between ribociclib and abemaciclib. One possible explanation is the diarrhea commonly associated with abemaciclib, which may increase CV risk through electrolyte imbalances.36 Moreover, the smaller sample size of patients using ribociclib and abemaciclib in our study may have contributed to the lack of statistical significance.
The long-term consequences of MACE contribute to a substantial increase in health care costs, including frequent hospitalizations, medications, outpatient visits, and loss of productivity.37 One United States–based study using health claims and electronic health record data found that patients who experienced MACE incurred nearly $44,000 higher adjusted 1-year health care costs compared with those without MACE.38 These costs are likely even greater in patients with cancer due to the complexity of managing both cancer and CV disease. Another United States–based study using the National Health Interview Survey found that financial toxicity, defined as food insecurity, delayed medical care due to cost, and difficulty paying medical bills, was significantly higher among patients with both cancer and atherosclerotic CV disease (ASCVD) compared with those who had cancer or ASCVD alone.39
Notably, we observed lower prescription costs in patients with hypertension and MACE compared with those without these conditions. This discrepancy may be due to factors such as cost-sharing arrangements, access to financial assistance programs, or a greater reliance on generic medications. However, it may also indicate potential undertreatment of CV risk factors, highlighting the critical need for specialized cardio-oncology care to optimize risk factor management and ultimately reduce overall health care costs.
Given the high financial cost of CDK4/6 inhibitors, the health care and patient cost burden is even more pronounced for patients with breast cancer and MACE. In our study, patients with MACE had significantly higher total health care costs than those without MACE, likely driven by increased ED and outpatient visits. Notably, prescription costs were lower in the MACE cohort, possibly due to treatment discontinuation of expensive medications like CDK4/6 inhibitors following CV adverse events. These findings highlight the importance of addressing CV complications in patients with breast cancer receiving CDK4/6 inhibitors to mitigate the financial burden on health care systems.
Several strategies can help mitigate the CV impact of CDK4/6 inhibitors in patients with breast cancer. These strategies include comprehensive CV screening prior to initiating CDK4/6 inhibitor therapy. A baseline assessment of CV risk factors (eg, hypertension, diabetes, dyslipidemia, prior chemotherapy) and preexisting CV disease (eg, atrial fibrillation, arrhythmia) is crucial for determining the most appropriate follow-up plan. A baseline electrocardiogram (ECG), along with serial ECG monitoring during treatment, can help detect any QTc prolongation.40 In addition to baseline assessments, a personalized approach to CDK4/6 inhibitor selection should be used for each patient. Previous studies have shown that the benefits of these inhibitors are independent of patient or breast cancer characteristics (eg, menopausal status, age, hormone receptor expression, prior treatments).41,42 Therefore, our findings serve as an essential resource for patient care, because understanding the differing cardiotoxic profiles of palbociclib, ribociclib, and abemaciclib can assist clinicians in making informed treatment decisions to optimize both cancer-specific and overall patient outcomes.36 After initiating CDK4/6 inhibitor therapy, periodic monitoring of CV function is recommended, including regular blood pressure checks and management, arrhythmia surveillance with periodic ECGs and event monitoring if indicated, and cardiomyopathy assessment using cardiac imaging modalities such as 3-dimensional echocardiography, myocardial strain assessment, and, if needed, cardiac MRI.40
Limitations
Our study has several limitations. First, the analysis relied on a large claims database, which lacks certain important covariates such as laboratory values and socioeconomic status. To mitigate this, we included all available patient- and disease-related variables and applied propensity score matching to reduce confounding and approximate certain aspects of RCTs. Additionally, our definition of hypertension relied on ICD-10 diagnosis codes from claims data rather than clinical values such as systolic or diastolic blood pressure, potentially underestimating hypertension prevalence. Second, we compared costs between patients with more than one MACE event and those without MACE. The MACE cohort may be highly heterogeneous due to varying disease severity, which could affect the precision of our findings. Third, we did not account for dose modifications of CDK4/6 inhibitors, which may influence the incidence of adverse events such as MACE and hypertension. Future studies using treatment-varying models are needed to evaluate these effects. Fourth, our reported health care costs include all incurred expenses during the follow-up period and do not isolate costs specifically related to CV events, potentially reflecting costs from other adverse events such as myelosuppressive complications. Future studies should aim to attribute costs more precisely to CV outcomes. Finally, the generalizability of our results is limited, because our analysis included only patients with commercial insurance. Prospective studies are needed to explore strategies for optimizing both the safety and effectiveness of CDK4/6 inhibitors in this high-risk population.
Despite these limitations, our study has several strengths. We used real-world data, which provides insights based on routine clinical practice, reflecting the outcomes of diverse patient populations outside the controlled settings of RCTs. Additionally, our study provides a comprehensive clinical and economic perspective by evaluating both the incidence and cost of MACE in patients with breast cancer receiving CDK4/6 inhibitors, offering valuable information for health care professionals and policymakers.
Conclusions
Our study highlights the variability in CV adverse events among the different CDK4/6 inhibitors used in breast cancer treatment. Palbociclib demonstrated a statistically significant lower risk of MACE compared with ribociclib, whereas abemaciclib showed a potential lower risk that did not reach statistical significance, warranting further investigation. Patients who developed MACE incurred substantially higher health care costs, underscoring the need for CV risk mitigation strategies in this population.
References
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