Published online before print December 18, 2006, doi: 10.1161/CIRCULATIONAHA.106.650176
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(Circulation. 2007;115:27-33.)
© 2007 American Heart Association, Inc.
Epidemiology |
Statins and the Risk of Lung, Breast, and Colorectal Cancer in the Elderly
From the Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass.
Reprint requests to Soko Setoguchi, MD, DrPH, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 1620 Tremont St, Suite 3030, Boston, MA 02130. E-mail ssetoguchi{at}partners.org
Received July 11, 2006; accepted October 23, 2006.
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Abstract |
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Background— Although most randomized trials and meta-analyses suggest a slight or no increase in the risk of cancer in statin users, results from observational studies have been conflicting, and some have even suggested a large protective effect of statins on certain cancers. Long-term statin users tend to be healthier, less frail, and more adherent to therapy than nonusers, however. This could explain such apparent "protective" effects.
Methods and Results— We conducted the present cohort study by linking data from a large state drug benefit program with cancer registry data and Medicare healthcare utilization data. We identified all initiators of statins; initiators of glaucoma medications, another preventive drug, served as a comparison group. Outcomes included all registry-identified cases of colorectal, lung, and breast cancer. Multivariable Cox proportional models were used to adjust for confounding. Patient characteristics were similar in both groups, but statin initiators (n=24 439) were slightly younger and used some services more frequently than glaucoma drug initiators (n=7284). The mean follow-up was 2.9 years, with the longest follow-up being 8.4 years. Incidence rates of colorectal, lung, and breast cancers in both groups were very similar to rates in the general population. Adjusted hazard ratios were 0.96 (95% CI, 0.70 to 1.31) for colorectal cancer, 1.11 (95% CI, 0.77 to 1.60) for lung cancer, and 0.99 (95% CI, 0.74 to 1.33) for breast cancer.
Conclusions— These data from a large population of typical older patients who began using statins indicate that it is unlikely that statins confer a clinically important decrease or increase in the risk of colorectal, lung, or breast cancer over the durations studied.
Key Words: statins • cancermorbidity • age
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Introduction |
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Multiple randomized controlled trials (RCTs) have demonstrated the beneficial effects of statins on cardiovascular morbidity and mortality in a variety of populations.1–7 The extensive evidence has led to widespread use of these drugs.8 Recent epidemiological studies have suggested that statins might reduce the risk of several cancers. As a result, statins are now being studied in clinical trials for cancer prevention.9
Clinical Perspective p 33
However, there is also evidence to suggest an opposite effect of statins on cancer in an RCT of elderly patients.6 The first concern about a possible association between statins and cancer followed a review of rodent studies that indicated that statins promoted cancer at concentrations equivalent to those commonly prescribed in humans.10 Subsequently, 4 meta-analyses of RCTs showed no increase or decrease in the risk of cancer.6,11–13 However, these trials have been criticized for having relatively short-term follow-up of highly selected groups of patients.
Although selected populations and short-term follow-up can be addressed in observational studies, the results of earlier observational studies are conflicting.14–21 Some observational studies that focused on the elderly population reported a significant protective effect,14,20,22 in contrast to RCT data in the elderly.6 Because long-term users of statins tend to be healthier, less frail physically and cognitively, and more adherent to therapy and screening than nonusers,23–26 these studies may have failed to adjust fully for these factors, possibly leading to residual confounding. With these methodological issues in mind, we conducted a cohort study using glaucoma drug initiators as a comparison group to assess the effect of statins on several specific common cancers in a large elderly population.
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Methods |
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Data Sources and Patients
We conducted a cohort study linking data on drug utilization and the Pharmaceutical Assistance Contract for the Elderly in Pennsylvania between January 1, 1994, and May 31, 2003, with healthcare utilization data from Medicare and Pennsylvania State Cancer Registry data. Pharmaceutical Assistance Contract for the Elderly is a state program of reimbursement for drug expenses for nonindigent elderly (age
65 years) who meet criteria for an annual income (<$13 000 if single and <$16 200 if married). The Medicare/Pharmaceutical Assistance Contract for the Elderly data provide basic demographic information and coded diagnostic, procedural, and pharmacy-dispensing information. The quality and completeness of Medicare claims data and Pharmaceutical Assistance Contract for the Elderly dispensing data are well characterized.27–29 The Pennsylvania Cancer Registry is a population-based registry that routinely collects data on demographics, primary tumor site, morphology, and stage at diagnosis for all cancer patients in that state. It is certified as "gold" (the highest quality) by the North American Association of Central Cancer Registries.30 The Institutional Review Board of the Brigham and Women’s Hospital approved the present study, and data-use agreements were established. All potentially traceable personal identifiers were removed from the data before analyses to protect patients’ privacy. The study population consisted of all subjects aged 65 years or older who were enrolled in Medicare and the drug benefit programs from 1994 to 2003. To ensure active system use, subjects were required to have had at least 1 clinical encounter and a prescription for any drug during each of 2 consecutive 6-month periods before cohort entry. Patients were excluded if they had a previous diagnosis of a cancer of interest recorded in the registry (1988 to 2003) before cohort entry.
Cohort Definition
We first identified all patients who filled a prescription for a statin during the period 1994–2002. To achieve a more homogeneous mix of users with regard to disease risk, we restricted the cohort to initiators of statins by ensuring that the patients had not filled a prescription for a statin for at least 12 months before the first prescription. We studied statin initiators to reduce the potential for attrition of susceptible individuals because of side effects or treatment failures, which could introduce bias.31 The design also allowed us to account for duration of exposure. As a comparison group, we identified initiators of glaucoma drugs in the same study population. Users of glaucoma drugs were selected as a reference group for the following reasons. Previous studies suggested that long-term users of statins tend to be healthier, less frail physically and cognitively, and more adherent to therapy and screening than nonusers.24,25 Glaucoma drugs are another type of preventive drug, and their users are likely to have characteristics similar to those of statin users with regard to health-seeking behavior and adherence to other preventive procedures. We have previously found that statins and glaucoma drugs were both prescribed less frequently to subjects at the end of life,23 and there is no evidence that glaucoma drug users pose an increased risk of cancer compared with the general population.32,33
Exposure Definition
Adherence to statin use declines most rapidly during the first 6 months, and these nonadherent users are likely to have very different characteristics with regard to health-seeking behaviors and/or preventive procedures.24,34,35 It is also difficult to establish the association between statin use and the occurrence of cancer in nonadherent patients. Therefore, we required statin initiators to fill 3 or more prescriptions of any statin (lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin, or cerivastatin) during the first 180 days after the first prescription of a statin. To ensure the comparability of the comparison group, the same criteria for adherence were applied to glaucoma drug users. Statin users who had taken glaucoma drugs previously or were taking them presently were excluded from the analyses (and vice versa for glaucoma drug users). We assumed an induction period of 180 days, so follow-up started 180 days after the first prescription was filled.
Study Outcomes
Subjects were censored at (1) the occurrence of a defined cancer end point, (2) initiation of the comparison drug (eg, initiation of glaucoma drug in statin users), (3) failure to fill 2 prescriptions of the exposure drug every 6 months, (4) death, (5) migration out of the healthcare system, or (6) end of the study period (May 31, 2003), whichever came first. The primary study end points were a new diagnosis of breast, colorectal, or lung cancer according to the cancer registry data. For colorectal and breast cancer, we excluded in situ cancer from the primary analyses because detection of in situ cancer is more likely to be driven by patients’ adherence to screening procedures. In a secondary analysis, these cases were included. The event date for each case was defined as the date of diagnosis recorded in the registry.
Potential Confounding and Its Measurement
We assessed demographic variables, documented risk factors for the selected cancers (inflammatory bowel disease, benign mammary dysplasia, arthritis, estrogen use, use of nonsteroidal antiinflammatory drugs, obesity, and tobacco abuse), prevention-related activities (mammography, gynecologic examination, pap smear, colonoscopy, and stool occult blood), and healthcare utilization (Charlson comorbidity score, number of physician visits, distinct generic medicines taken, prior hospitalization, and prior nursing home stay) during the 12 months before the index date. These covariates were identified with International Classification of Diseases, 9th Revision, diagnostic codes, current procedural terminology procedure codes, and/or prescription information.
Statistical Analysis
First, we compared crude incidence rates of the study cancers in the present cohort to those in the general population. The rates for the general population were calculated by standardizing the Surveillance, Epidemiology, and End Results cancer rates for age and gender. In the present study cohort, we excluded the first 6 months after initiation of the drug from this rate calculation to avoid immortal person-time bias and to account for 6 months of induction time.36 We used multivariable Cox proportional hazards regression to estimate the effects of statin use on incidence of cancer compared with glaucoma drug use. Statistical significance was assessed with 95% CIs. We tested the proportional hazards assumption by including an interaction term between time and exposure in the model. All statistical analyses were performed with the SAS statistical program (version 9, SAS, Cary, NC).
Assessment for Unmeasured Confounding With External Data and Sensitivity Analyses
Using data from the Medicare Current Beneficiary Survey (MCBS), we assessed the balance of variables not measured in our healthcare utilization data. The MCBS is conducted in a sample of Medicare beneficiaries selected each year to be representative of the current Medicare population, including both aged and disabled beneficiaries living in the community or in institutions. Previously, the data have been used to estimate the likelihood of confounding bias.37 We identified users of statins and glaucoma drugs in MCBS data from 1999 to 2001 and excluded subjects with history of breast, colorectal, or lung cancers. We estimated the prevalence of smoking status, body mass index, functional status, education, and aspirin use in users of statins versus glaucoma drugs.
We further conducted quantitative sensitivity analyses to assess the impact of important unmeasured confounders, ie, smoking, aspirin use, and family history of cancer, using the estimated prevalence of these covariates in glaucoma drug users from MCBS data.38 We assumed that the rate ratio (RR) of the association between smoking (ever versus never) and lung cancer was 11.6 from the estimates for current smoking versus nonsmoking in US data39 and that the effect of aspirin was RR=0.6 for colorectal cancer.40 Because prevalence of family history of cancer was not available in MCBS data, we assumed the prevalence of family history of lung and breast cancer was 15%41,42 in glaucoma drug users, with an effect size of approximately RR=2.0 (RR=1.8 for lung cancer, with greater risk in younger subjects,43 and RR=1.5 for breast cancer in elderly women44). We did not perform sensitivity analyses for family history with regard to colorectal cancer because family history is a strong risk factor in younger populations (especially those aged <45 years) but not in older populations.45
The authors had full access to the data and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
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Results |
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Study Patients and Their Characteristics
After the application of exclusion and inclusion criteria, the cohort consisted of 24 439 statin initiators and 7284 glaucoma drug initiators. The characteristics of the study population measured during the 12-month period before the initiation of either drug class are shown in Table 1. In general, glaucoma users were slightly older than statin users but had comparable characteristics for health service utilization, use of preventive services, and observable risk factors for the cancers of interest.
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Incidence Rates of Cancers
Table 2 shows the number of cancers, person-years of follow-up, and incidence of colorectal, lung, and invasive breast cancer in the cohort and in the general population standardized for age and gender with Surveillance, Epidemiology, and End Results data.46 The majority of cases in statin users (61% of colorectal cancers and 77% of breast cancers) occurred after 3 years of drug use, whereas 41% of lung cancers occurred after 3 years. The cancer rates we observed in the present study population were comparable to cancer incidence rates in the US general population.
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Cancer Risk in Statin Users
Table 3 shows unadjusted, age/gender/race–adjusted, and multivariable adjusted hazard ratios (HRs) of invasive colorectal cancer, lung cancer, and invasive breast cancers. The total numbers of cancers after the exclusion of in situ cancers were 233 for colorectal cancer and 268 for breast cancer. We found no meaningful increase or decrease in the risk of cancers in statin users compared with that in glaucoma drug users. In a secondary analysis, we included in situ cases in the outcome for colorectal and breast cancers. The multivariable adjusted HRs including in situ cases were unchanged: 0.97 (95% CI, 0.74 to 1.28) for colorectal cancer and 0.93 (95% CI, 0.68 to 1.26) for breast cancer. We also examined the effects of different types of statins. The HR estimates for hydrophobic statins (simvastatin, lovastatin, fluvastatin, and atorvastatin47) and for pravastatin were not meaningfully different from the overall result (point estimates ranged from 0.87 to 1.18).
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The test for proportional hazard was statistically significant for breast cancer (P=0.003), which indicates that the effect of statin use might be different over time. It was not significant for colorectal cancer (P=0.39) or lung cancer (P=0.65). Table 4 shows point estimates for short-term effects of statins (
3 years) and longer-term effects (>3 years). The short-term effect of statins tended to be protective for breast cancer.
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Balance in Unmeasured Factors in MCBS Data
Compared with glaucoma drug users, statin users were more educated, less functionally limited, had a slightly higher mean body mass index, and were more likely to have been smokers and to take aspirin (Table 5).
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Sensitivity Analyses on Unmeasured Confounders
The Figure shows the impact of 3 important unmeasured confounders on our observed null effect of statin use on incident cancer. Given the estimated prevalence of smoking and aspirin use in the MCBS survey data, we concluded that the corrected HR would be 0.90 for smoking and 1.02 for aspirin use (see the 2 circled points in the Figure). Because there is no evidence that family history of cancer is associated with statin use versus glaucoma drug use, we can assume that the prevalence in statin users would reasonably be in the range of 5% to 30% compared with the prevalence of 15% in the general population; then, the corresponding range of corrected HR was 0.87 to 1.07.
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Discussion |
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We estimated the risk of common solid cancers among new users of statins compared with new users of glaucoma drugs, and we found no significant increase or decrease in the risk of cancers among statin users. The present study has several strengths compared with earlier studies. First, we restricted the analysis to new users of statins, eliminating the biases that can occur when prevalent drug users are included.31 Second, we used a comparison group likely to have similar characteristics in health-seeking behaviors and adherence to screening procedures.23 Third, the present study considered of a very large group of older adults at high risk of cancer. Finally, we used registry-validated cancer diagnosis to measure outcomes.
An overview11 of RCTs of statins reported no significantly increased risk of cancer (RR, 1.07; 95% CI, 0.90 to 1.26), and 3 meta-analyses found the same result.6,12,13 A nested case-control study using healthcare utilization databases in Quebec, Canada, compared statin users with resin users aged 65 years and older and found no increase but a decrease in cancer incidence with a median follow-up period of 2.7 years.14 Population-based studies using a health-services database in Saskatchewan, Canada,15 and the United Kingdom’s General Practice Research Database16,17 suggested that statins may be associated with a marginally increased risk of breast cancer or no association with overall cancer risk. Two studies using Danish18 and Dutch19 health-service databases found a 20% reduction in overall cancer. Three other studies in younger women in the United States (Case-Control Surveillance Study,48 Nurses’ Health Study,49 and a population-based case-control study of 3 Washington counties50) showed no significant reduction of the risk for invasive breast cancer (RR ranged from 0.9 to 1.2). Most recently, large cohort studies in the United States found no association between statin use and colorectal51 and breast52 cancer. Although the populations in most trials and these observational studies were relatively young compared with the present study population, our findings are similar to the meta-analyses14,20,22 and the most recent studies,51,52 and the point estimates from all the other studies are included within the 95% CIs of our estimates.
The results of the present study exclude the strong protective effect of statins found in observational studies in the elderly by Cauley et al22 and Poynter et al.20 Cauley et al22 conducted a prospective cohort study in US elderly woman (aged 65 years) and reported a 68% reduction in the risk of breast cancer in statin users. A population-based case-control study in northern Israel by Poynter et al20 reported a 47% reduction in colorectal cancer among long-term statin users (5 years) compared with short-term users or nonusers among the elderly (aged 60 years). As we have pointed out,53 however, long-term statin users are likely to be systematically different from nonusers of statins. Health-seeking behavior and the healthier lifestyle of long-term compliant statin users may independently lower the risk of colorectal cancer. In addition, prevention-oriented statin users may be more likely to have precancerous colorectal polyps detected and removed early, which would make statins appear protective. These studies by Poynter et al20 and Cauley et al22 may have failed to adjust adequately for these factors, likely leading to residual confounding. The present study attempted to adjust for these possible biases by choosing equally compliant glaucoma drug users as a comparison group. These patients take another kind of preventive drug that, like statins, is less frequently prescribed to subjects at the end of life.23,54 We found that use of preventive procedures in glaucoma drug users was comparable to that of statin users (Table 1).
Long-term statin users have survived and stayed healthy enough to continue to take statins. As a result, in many studies, patients who are vulnerable or susceptible to cancer or other morbid conditions drop out of the long-term statin user cohort, leaving those who are healthier and less susceptible to the risk of cancer (attrition of susceptible individuals). This bias can be avoided by employing a study design that enrolls only initiators of statins or a comparison drug and by comparing their risk at the same point over the course of drug exposure in a Cox model, as we did here. A naïve case-control design (without risk-set sampling) simply comparing long-term users of statins with nonusers has difficulty handling this bias.
The present results raise the possibility that the short-term effect of statins on breast cancer might differ from that of long-term use, with short-term use appearing modestly protective and long-term use seeming to raise the risk slightly, although not significantly. Although we have adjusted for screening behaviors of the study patients, it is possible that statin users had relatively more extensive screening before they reached 65 years of age that was not captured in our data and therefore had fewer events during the first years after their enrolment into Medicare and initiation of statins. The present data do not rule out a possibly increased risk of cancer for long-term statin users beyond the range of our data.
Several limitations of the present study should be noted. A number of possible confounders were not measured in the data (eg, aspirin use and family history of cancer) or were measured incompletely (eg, tobacco use and obesity). These unmeasured risk factors might have biased results if they were differentially associated with statin versus glaucoma drug use. We might have been able to reduce much of this confounding by the choice of comparison group. Using MCBS data, we found that some of the possible confounding factors unmeasured in our data, such as body mass index, smoking, functional status, and aspirin use, were slightly imbalanced; however, sensitivity analyses showed that these differences were not substantial enough to cause significant bias in our estimates. Finally, although we believe that new glaucoma drug users are a more valid comparison group than nonusers of statins, the size of the group was smaller than the statin user group and resulted in less precise estimates.
The mean duration of drug use in the present study population was 2.9 years, slightly longer than that of the RCTs criticized for having a relatively short follow-up.6,11–13 Nonetheless, the study population included patients with various durations of follow-up (maximum of 8.4 years), and 40% of the patients had a follow-up of more than 3 years, with 60% of cancers occurring after 3 years of follow-up. Assessment of the possibility of different risk with longer use will require studies with greater exposure durations.
The present data indicate that in the first several years of statin use, it is unlikely that elderly patients have a clinically important decrease or increase in the risk of colorectal, lung, or breast cancer compared with elderly patients using other, unrelated preventive medications. The present data do not rule out a possibly increased risk of long-term statin use beyond the period of exposure studied, however.
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Acknowledgments |
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Disclosures
Dr Glynn reports that he has a contract with AstraZeneca to serve as the independent statistical monitor of its trial of Crestor (rosuvastatin; JUPITER trial). The remaining authors report no conflicts.
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Guest Editor for this article was Gregory L. Burke, MD, MSc.
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