The Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) clinical trial, including 1,873 patients found an increased risk for cancer with lipid-lowering therapy with ezetimibe/simvastatin 10/40 mg/day, relative to placebo. In a registry-based follow-up study over 21 months from the conclusion of the SEAS trial, new incident cancer and total mortality were investigated in the SEAS study cohort from Denmark, Finland, Norway, Sweden, and the United Kingdom. Among 1,359 subjects eligible for follow-up (73% of the original total cohort), 1,194 had no history of cancer (primary follow-up cohort). New cancers and deaths were identified in the national cancer and mortality registries and classified by an Expert Review Committee. Data were analyzed using Cox proportional-hazards models of new cancers and mortality during follow-up according to treatment group assigned in the SEAS base study and with age, gender, smoking history, and previous cancers as covariates. The primary follow-up cohort had 12 patients with new cancers in the ezetimibe/simvastatin group and 22 in the placebo group (hazard ratio 0.55, 95% confidence interval 0.27 to 1.11), indicating no significant difference between the treatment groups. During follow-up, 43 patients assigned to ezetimibe/simvastatin and 33 assigned to placebo died (hazard ratio 1.29, 95% confidence interval 0.82 to 2.03). In conclusion, in this registry-based observational follow-up study of the original SEAS study patient population, treatment with ezetimibe/simvastatin was not associated with an increased risk for cancer or mortality in the 21-month period after the completion of the original SEAS study.
The Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study was a randomized, double-blind, placebo-controlled, multicenter clinical trial in patients with mild to moderate asymptomatic aortic stenosis that assessed the effect of lipid lowering with ezetimibe/simvastatin 10/40 mg/day (n = 944) compared with placebo (n = 929) on cardiovascular outcomes. Analyses of safety data from the base SEAS study indicated an imbalance in cancer-related serious adverse experiences between groups, with statistically significantly more cancers and cancer deaths observed in patients assigned to ezetimibe/simvastatin than in those receiving placebo. These differences were not related to any particular type of cancer and did not become significantly larger with more prolonged treatment. In light of the unexpected cancer findings in SEAS, the follow-up of study subjects included in the trial was extended for an additional 21 months after the randomized treatment period, to further observe the incidence of cancer and mortality in the unique SEAS patient population. For feasibility reasons, the follow-up study was restricted to settings in which information on clinical outcomes such as cancer and deaths is identifiable from routinely available national health registries. The aim of this observational registry study was to estimate risks for incident cancers and all-cause mortality. The prespecified hypotheses were that the risk for developing cancer and for death during the follow-up period were similar for patients originally allocated to treatment with ezetimibe/simvastatin 10/40 mg/day compared with patients originally allocated to placebo.
Methods
This was an observational, multinational, follow-up study (protocol 043-11, ClinicalTrials.gov identifier NCT01077830 ) of the SEAS trial ( ClinicalTrials.gov identifier NCT00092677 ), designed to estimate the risk for cancer and all-cause mortality during a 21-month follow-up period after the original study ended on March 3, 2008. A 21-month follow-up period ending December 31, 2009 was chosen to allow adequate follow-up within a reasonable time frame and was consistent with available registry data, which are released on a calendar-year basis, with a lag of approximately 12 to 18 months.
No therapeutic or prophylactic agent was administered in the SEAS follow-up study, and no information was available on the use of lipid-lowering treatment after the base study. National registries of cancer, death, and hospitalizations have provided data in line with the rules and regulations pertaining to the respective registries. All data were obtained after receiving approval from the relevant authorities. Per national regulations, patients from the United Kingdom were given the opportunity to opt out of inclusion in the registry search.
Five of the 7 countries that participated in the SEAS base study also participated in the follow-up study, including Sweden, Denmark, Norway, Finland, and the United Kingdom. Patients from Germany were not included, because national cancer and mortality registries were not available. Inclusion of the 17 patients from Ireland also was not feasible, because of limitations on research use of the Irish registries.
Of the original total cohort of 1,873 patients, 1,392 patients (74%) from Denmark, Finland, Norway, Sweden, and the United Kingdom were alive at the end of the SEAS clinical trial on March 3, 2008. However, 33 patients were excluded from the follow-up analysis because of incomplete clinical trial data (n = 16). Seventeen patients were lost to follow-up, including 13 patients from the United Kingdom who opted out of the follow-up study and 4 patients from Northern Ireland whose data were received after the analysis cut-off date, established as December 21, 2012. Accordingly, we searched the registries for follow-up data on 1,359 patients, including those with or without a history of cancer before the follow-up study. This population constituted the follow-up total cohort, representing 73% of the total SEAS patient population.
Patients from the 5 countries with death and cancer registries, who were alive at the end of the base study and had no cancer before the follow-up period, were defined as the primary analysis population and are referred to as the follow-up primary cohort. Hence, the primary analysis population for cancer incidence excluded patients with cancer diagnosed before start of the follow-up study on March 4, 2008, because these patients were more likely to present new secondary or recurrent cancer. History of previous cancer was determined through review of the medical history and serious adverse event data from the base SEAS study. Characterization of cohorts eligible for follow-up is listed in Table 1 .
| Variable | Follow-Up Total Cohort | Follow-Up Primary Cohort | ||
|---|---|---|---|---|
| Active Drug ∗ (N = 677) | Placebo (N = 682) | Active Drug ∗ (N = 595) | Placebo (N = 599) | |
| Country | ||||
| Denmark | 136 (20.1%) | 137 (20.1%) | 121 (20.3%) | 122 (20.4%) |
| Finland | 107 (15.8%) | 100 (14.7%) | 95 (16.0%) | 90 (15.0%) |
| Norway | 184 (27.2%) | 192 (28.2%) | 160 (26.9%) | 169 (28.2%) |
| Sweden | 189 (27.9%) | 182 (26.7%) | 168 (28.2%) | 158 (26.4%) |
| United Kingdom | 61 (9.0%) | 71 (10.4%) | 51 (8.6%) | 60 (10.0%) |
| Age at start of follow-up | ||||
| Less than 50 years | 4 (0.6%) | 3 (0.4%) | 4 (0.7%) | 3 (0.5%) |
| 50 to 59 years | 92 (13.6%) | 91 (13.3%) | 86 (14.5%) | 87 (14.5%) |
| 60 to 69 years | 160 (23.6%) | 189 (27.7%) | 148 (24.9%) | 175 (29.2%) |
| 70 to 79 years | 250 (36.9%) | 234 (34.3%) | 214 (36.0%) | 194 (32.4%) |
| 80 years and older | 171 (25.3%) | 165 (24.2%) | 143 (24.0%) | 140 (23.4%) |
| Gender | ||||
| Female | 267 (39.4%) | 272 (39.9%) | 239 (40.2%) | 239 (39.9%) |
| Male | 410 (60.6%) | 410 (60.1%) | 356 (59.8%) | 360 (60.1%) |
| Smoking status at trial baseline | ||||
| No | 297 (43.9%) | 298 (43.7%) | 259 (43.5%) | 256 (42.7%) |
| Ex-User | 231 (34.1%) | 258 (37.8%) | 199 (33.4%) | 228 (38.1%) |
| Yes | 149 (22.0%) | 126 (18.5%) | 137 (23.0%) | 115 (19.2%) |
Data were obtained from the national cancer and mortality registries in Denmark, Norway, Finland, and Sweden and from the corresponding regional and national registries in the United Kingdom for all SEAS base study patients known to be alive at the completion of the randomized clinical trial period. Descriptions of the Nordic and United Kingdom cancer registries have been previously published. Data collected included cancer diagnosis (International Classification of Diseases, 10th Revision, coding) and date of cancer diagnosis, date of death, and all registered causes of death (International Classification of Diseases, 10th Revision, coding). The data set for analysis comprised the follow-up data together with data from the original SEAS clinical trial on demographics, medical history, and cancer events before and during the SEAS base study.
An independent external Expert Review Committee comprised of 1 cardiologist and 2 oncologists was established to evaluate and classify all events registered as part of the follow-up study. Cancer events were classified according to the following groups: (1) definite new case not related to previously registered cancer before March 3, 2008 (if any), (2) definite recurrence of previously registered cancer, or (3) not classifiable regarding temporal relation. In addition, deaths were classified according to the following groups: cancer deaths, cardiovascular deaths (including cerebrovascular deaths), noncardiovascular noncancer deaths (including infections and traumas), and unclassifiable.
Descriptive statistics are presented using numbers and percentages. Differences in incident cancers between the initial treatment groups were analyzed by using hazard ratios (hazard of group randomized to ezetimibe/simvastatin in the base study divided by hazard of group randomized to placebo in the base study) and its 95% confidence intervals (Wald method) obtained from a multivariate Cox proportional-hazards model. Covariates included age at start of follow-up, gender, nationality, smoking status at the original SEAS clinical trial baseline, and history of cancer before follow-up (yes or no), which might be potential confounders. Patients without recorded incident cancer were censored on December 31, 2009. The proportional-hazards assumption was checked graphically. We conducted separate analyses in the follow-up total cohort and the follow-up primary cohort. To assess differences in all-cause mortality, we conducted an analysis of time until death of any cause, using a similar approach and the same covariates. Patients without recorded death were censored on December 31, 2009. Statistical significance level was set at 5%, corresponding to 95% confidence intervals around point estimates.
Results
A total of 47 registrations of neoplasms with dates of diagnosis within the follow-up period were reported for the entire cohort. According to the Expert Review Committee classification, 1 registration of a benign neoplasm of the bladder was considered not to be cancer. Furthermore, 1 subject had 2 gastrointestinal cancers registered with identical dates of diagnosis and was considered to represent only 1 case of cancer. Among the remaining 45 subjects with 45 registrations of cancer, 1 case was unclassifiable because it could not be determined whether it was a new cancer or a recurrence of a previously diagnosed nonmelanoma skin cancer. Among the 44 cases of cancer considered to be new (incident) during follow-up, there were 10 cases of nonmelanoma skin cancer, with 1 case in the ezetimibe/simvastatin 10/40 mg treatment group and 9 cases in the placebo group. The new (incident) cases of cancer are listed in Table 2 , grouped by the follow-up cohort type and main location of the cancer.
