Statin Use and the Risk of Venous Thromboembolism in Women Taking Hormone Therapy.

Importance: Although hormone therapy (HT) in perimenopausal women is associated with increased risk for venous thromboembolism (VTE), it is unclear to what extent statins may mitigate this HT-associated risk. Objective: To estimate VTE risk in women aged 50 to 64 years taking HT with or without statins. Design, Setting, and Participants: This nested case-control study analyzed data from a commercially insured claims database in the US. Eligible participants included women aged 50 to 64 years with at least 1 year of continuous enrollment between 2008 and 2019. Data analysis occurred from January 2022 to August 2023. Exposure: Filled prescriptions for estrogens, progestogens, and statins were recorded in the 12 months prior to index. Recent HT was defined as any estrogen or progestogen exposure within 60 days before the index date. Current statin exposure was defined as 90 or more days of continuous exposure prior to and including the index date. Statin intensity was defined by the statin exposure 30 days prior to index. Main Outcomes and Measures: Cases were identified with VTE diagnoses (diagnostic codes) preceded by at least 12 months without VTE and followed within 30 days by anticoagulation, an inferior vena cava filter placement, or death. Controls were matched to cases (10:1) on date and age. Conditional logistic regression models estimated risk for HT and statin exposures with odds ratios (OR), adjusted for comorbidities. Conditional logistic regression models were used to estimate VTE risk for HT and statin exposures with odds ratios (ORs), adjusted for comorbidities. Intensity of statin therapy was measured as a subgroup analysis. Results: The total sample of 223 949 individuals (mean [SD] age, 57.5 [4.4] years) included 20 359 cases and 203 590 matched controls. Of the entire sample, 19 558 individuals (8.73%) had recent HT exposure and 36 238 individuals (16.18%) had current statin exposure. In adjusted models, individuals with any recent HT exposure had greater odds of VTE compared with those with no recent HT exposure (OR, 1.51; 95% CI, 1.43-1.60). Individuals receiving current statin therapy had lower odds of VTE compared with those with no current statin exposure (OR, 0.88; 95% CI, 0.84-0.93). When compared with those not recently taking HT or statins, the odds of VTE were greater for those taking HT without statins (OR, 1.53; 95% CI, 1.44-1.63) and for those taking HT with statins (OR, 1.25; 95% CI, 1.10-1.43), but were lower for those taking statins without HT (OR, 0.89; 95% CI, 0.85-0.94). Individuals taking HT with statin therapy had 18% lower odds of VTE than those taking HT without statins (OR, 0.82; 95% CI, 0.71-0.94) and there was greater risk reduction with higher intensity statins. Conclusions and Relevance: In this case-control study, statin therapy was associated with reduced risk of VTE in women taking HT, with greater risk reduction with high-intensity statins. These findings suggest that statins may reduce risk of VTE in women exposed to HT and that HT may not be contraindicated in women taking statins.

Incidence of venous thrombotic events and events of special interest in a retrospective cohort of commercially insured US patients.

OBJECTIVE: To estimate the US incidence of thrombotic events and related rare diagnoses. DESIGN: Claims-based retrospective cohort study of incidence. SETTING: US commercial health insurance administrative claims database. PARTICIPANTS: Adults 25-64 years of age between 2015 and 2019 with a minimum of 12 consecutive thrombosis-free months of continuous enrolment beginning 2014 were selected. MAIN OUTCOMES: Age (10-year intervals) and sex stratum-specific incidence rates per 100 000 person-years were determined for venous thromboembolism (VTE), cerebral venous thrombosis (CVT) and other major venous thrombotic events, and events of special interest, including immune thrombocytopenic purpura (ITP), haemolytic-uremic syndrome (HUS) and heparin-induced thrombocytopenia (HIT). RESULTS: Of 13 249 229 enrollees (half female/male), incidence of venous thromboembolic events (deep vein thrombosis (DVT), pulmonary embolism (PE), CVT or other major venous thrombotic conditions) was 247.89 per 100 000 person-years (95% CI: 245.96 to 249.84). Incidence of VTE was 213.79 with ICD codes alone (95% CI: 211.99 to 215.59) and 129.34 (95% CI: 127.95 to 130.75) when also requiring a filled anticoagulation prescription or an inferior vena cava (IVC) filter. Incidence was 6.37 for CVT (95% CI: 6.07 to 6.69), 26.06 for ITP (95% CI: 25.44 to 26.78), 0.94 for HUS (95% CI: 0.82 to 1.06) and 4.82 for HIT (95% CI: 4.56 to 5.10). The co-occurrence of CVT with either ITP or HIT (diagnoses within 14 days of one another) was 0.090 (95% CI: 0.06 to 0.13). Incidence tended to increase with age and was higher for women under 55. Incidence for CVT, HUS and CVT with ITP or HIT was higher for women in all age groups. Incidence of PE and CVT increased significantly over the 5-year period, while DVT rates decreased. CONCLUSIONS: These results are the first US estimates for the incidence of thrombotic and rare events of interest in a large, commercially insured US population. Findings provide a critically important reference for determining excess morbidity associated with COVID-19 and more generally for vaccine pharmacovigilance.

Trends in otitis media-related health care use in the United States, 2001-2011.

IMPORTANCE: Otitis media (OM) is a leading cause of pediatric health care visits and the most frequent reason children consume antibiotics or undergo surgery. During recent years, several interventions have been introduced aiming to decrease OM burden. OBJECTIVE: To study the trend in OM-related health care use in the United States during the pneumococcal conjugate vaccine (PCV) era (2001-2011). DESIGN, SETTING, AND PARTICIPANTS: An analysis of an insurance claims database of a large, nationwide managed health care plan was conducted. Enrolled children aged 6 years or younger with OM visits were identified. MAIN OUTCOMES AND MEASURES: Annual OM visit rates, OM-related complications, and surgical interventions were analyzed. RESULTS: Overall, 7.82 million unique children (5.51 million child-years) contributed 6.21 million primary OM visits; 52% were boys and 48% were younger than 2 years. There was a downward trend in OM visit rates from 2004 to 2011, with a significant drop that coincided with the advent of the 13-valent vaccine (PCV-13) in 2010. The observed OM visit rates in 2010 (1.00/child-year) and 2011 (0.81/child-year) were lower than the projected rates based on the 2005-2009 trend had there been no intervention (P < .001). Recurrent OM (≥3 OM visits within 6-month look-back) rates decreased at 0.003/child-year (95% CI, 0.002-0.004/child-year) in 2001-2009 and at 0.018/child-year (95% CI, 0.008-0.028/child-year) in 2010-2011. In the PCV-13 premarket years, there was a stable rate ratio (RR) between OM visit rates in children younger than 2 years and in those aged 2 to 6 years (RR, 1.38; 95% CI, 1.38-1.39); the RR decreased significantly (P < .001) during the transition year 2010 (RR 1.32; 95% CI, 1.31-1.33) and the postmarket year 2011 (RR 1.01; 95% CI, 1.00-1.02). Tympanic membrane perforation/otorrhea rates gradually increased (from 3721 per 100,000 OM child-years in 2001 to 4542 per 100,000 OM child-years in 2011; P < .001); the increase was significant only in the older children group. Mastoiditis rates substantially decreased (from 61 per 100,000 child-years in 2008 to 37 per 100,000 child-years in 2011; P < .001). Ventilating tube insertion rate decreased by 19% from 2010 to 2011 (P = .03). CONCLUSIONS AND RELEVANCE: There was an overall downward trend in OM-related health care use from 2001 to 2011. The significant reduction in OM visit rates in 2010-2011 in children younger than 2 years coincided with the advent of PCV-13. Although tympanic membrane perforation/otorrhea rates steadily increased during that period, mastoiditis and ventilating tube insertion rates decreased in the last years of the study.

Compliance with cervical cancer screening and human papillomavirus testing guidelines among insured young women.

OBJECTIVE: In December 2009, the American Congress of Obstetricians and Gynecologists (ACOG) recommended that women under 21 years old should not receive cervical cancer screening (Papanicolaou tests) or human papillomavirus (HPV) tests. This study examined whether clinicians stopped administering Papanicolaou and HPV tests among women younger than 21 years of age after new ACOG guidelines were issued. STUDY DESIGN: This study was a retrospective secondary data analysis of administrative claims data that included insurance enrollees from across the United States that examined the frequency of Papanicolaou tests and HPV tests among 178,898 nonimmunocompromised females 12-20 years old who had a paid claim for a well-woman visit in 2008, 2009, or 2010. Young women with well-woman examinations in each observed year were examined longitudinally to determine whether past diagnoses of cervical cell abnormalities accounted for Papanicolaou testing in 2010. RESULTS: The proportion of women younger than 21 years old that received a Papanicolaou test as part of her well-woman exam dropped from 77% in 2008 and 2009 to 57% by December of 2010, whereas HPV testing remained stable across time. A diagnosis of cervical cell abnormalities in 2009 was associated with Papanicolaou testing in 2010. However, a previous Papanicolaou test was more strongly associated with a Papanicolaou test in 2010. CONCLUSION: These data show that some physicians are adjusting their practices among young women according to ACOG guidelines, but Papanicolaou and HPV testing among insured women younger than 21 years of age still remains unnecessarily high.

Complications and continuation of intrauterine device use among commercially insured teenagers.

OBJECTIVE: Many U.S. health care providers remain reluctant to prescribe intrauterine devices (IUDs) to teenagers as a result of concerns about serious complications. This study examined whether 15-19-year-old IUD users were more likely to experience complications, failure, or early discontinuation than adult users aged 20-24 years and 25-44 years and whether there were differences in these outcomes between users of levonorgestrel-releasing intrauterine systems and copper IUDs. METHODS: A retrospective cohort study was conducted using health insurance claims obtained from a private insurance company of 90,489 women who had an IUD inserted between 2002 and 2009. Logistic regression models were used to estimate the odds of experiencing complications, method failure, or early discontinuation within 12 months of insertion by age group and type of IUD inserted. RESULTS: Serious complications, including ectopic pregnancy and pelvic inflammatory disease, occurred in less than 1% of patients regardless of age or IUD type. Women aged 15-19 years were more likely than those aged 25-44 years to have a claim for dysmenorrhea (odds ratio [OR] 1.4, confidence interval [CI] 1.1-1.6), amenorrhea (OR 1.3, CI 1.1-1.5), or normal pregnancy (OR 1.4, CI 1.1-1.8). Overall, early discontinuation did not differ between teenagers and women aged 25-44 years (13% compared with 11%, P>.05). However, use of the levonorgestrel-releasing intrauterine system was associated with fewer complications and less early discontinuation than the copper IUD in all age groups. CONCLUSIONS: The IUD is as appropriate for teenagers to use as it is for older women, with serious complications occurring infrequently in all groups. The levonorgestrel-releasing intrauterine system may be a better choice than the copper IUD as a result of lower odds of complications, discontinuation, and failure. LEVEL OF EVIDENCE: II.

Completion of the human papillomavirus (HPV) vaccine series among males with private insurance between 2006 and 2009.

Little is known about initiation and completion among males who received the HPV vaccine on an off-label basis before 2009. This study utilized administrative claims data from a private insurance company to examine completion of the 3 dose HPV series among 514 males who initiated the vaccine between 2006 and May of 2009. Frequencies of HPV vaccination were examined and multivariate logistic regression estimated the odds of completing the entire series within 365 days of initiation. We found that only 21% of male initiators completed all 3 vaccine doses within 12 months and completion decreased over time. Series completion did not vary significantly by provider type. These findings suggest that difficulties may be encountered in fully vaccinating enough males to achieve adequate herd immunity in the future.

Completion of the human papillomavirus vaccine series among insured females between 2006 and 2009.

BACKGROUND: Completion of the human papillomavirus (HPV) vaccine in a large percentage of young females is an important goal to prevent anogenital cancers associated with HPV. The current study examined whether the percentage of insured women who complete the vaccine series has changed across time, and how provider type and age at initiation affects rates of completion. METHODS: This retrospective cohort study used administrative data from a private insurance company. The study included 271,976 females in whom the HPV vaccine series was initiated and who had been continuously enrolled in their respective insurance plan for 365 days after vaccine initiation. Multivariate logistic regression was used to determine the odds of completing the vaccine series within 365 days after initiation. RESULTS: Females aged 13 years to 18 years, 19 years to 26 years, and ≥ 27 years were found to be less likely than those ages 9 years to 12 years to complete their HPV vaccine series. Obstetricians/gynecologists were more likely to administer vaccines to completers than pediatricians, whereas clinics, nurses, family care practitioners, and specialists were less likely to administer initial vaccines to completers compared with pediatricians. The results of the current study also found that females aged 9 years to 12 years and 13 years to 18 years had lower odds of completing the HPV vaccine series for each subsequent year compared with those aged 19 years to 26 years and ≥ 27 years. CONCLUSIONS: Among insured females in the United States, the percentage of females who complete the HPV vaccine series is dropping over time, especially among younger females, who are specifically targeted to receive the vaccine. Physicians need to stress the importance of completing all 3 vaccinations to their patients.

Continuation rates and complications of intrauterine contraception in women diagnosed with bipolar disorder.

OBJECTIVE: To estimate continuation rates, complications, and psychiatric hospitalizations among women with bipolar disorder using levonorgestrel-releasing or copper-containing intrauterine devices (IUDs) as compared with those using depot medroxyprogesterone acetate or sterilization for birth control. METHODS: Data for this cohort study were obtained from a nationwide health insurance claims database on an employed, commercially insured population. Women aged 18-44 years with a prior diagnosis of bipolar disorder (n=849) who were using the levonorgestrel intrauterine system, a copper-containing IUD, depot medroxyprogesterone acetate, or sterilization were evaluated. Outcomes included continuation rates over a 12-month interval, infectious and noninfectious complications, and hospitalizations for bipolar disorder or depression. RESULTS: Women using an IUD were more likely than those using depot medroxyprogesterone acetate to continue the method for at least 12 months (copper-containing IUD, 86%; levonorgestrel intrauterine system, 87%). In comparison, only 31% of those who initiated depot medroxyprogesterone acetate received three more injections during the next year (P<.001). No significant differences were noted in infectious or noninfectious complications by contraceptive type. Finally, no differences were observed in the number of hospitalizations for bipolar disorder or depression among the four contraceptive groups. CONCLUSION: More women with bipolar disorder continued using IUDs at one year than women using depot medroxyprogesterone acetate. The rates of complications and psychiatric hospitalizations were not different among women using an IUD, depot medroxyprogesterone acetate, or sterilization. LEVEL OF EVIDENCE: II.

Osteonecrosis of the jaw in older osteoporosis patients treated with intravenous bisphosphonates.

BACKGROUND: Intravenous bisphosphonate therapy has been linked to osteo-necrosis of the jaw among patients with cancer. Some patients with osteoporosis also receive intravenous bisphosphonates, although at lower total doses than those with cancer. OBJECTIVE: To examine the risk for jaw osteonecrosis among a population-based cohort of older adults receiving intravenous bisphosphonates for the treatment of osteoporosis. METHODS: Using a 5% national sample of Medicare beneficiaries, we identified 2296 patients treated with intravenous infusions of bisphosphonates for osteoporosis and other metabolic bone diseases between January 1, 2000, and December 31, 2007. We matched this cohort to 6865 bisphosphonate nonusers, at a 1:3 ratio, on age, race, sex, type of bone disease, and risk factors for osteonecrosis of the jaw. Patients were followed until December 31, 2007. The jaw toxicity outcomes included operations on the facial bones or jaw and diagnosis of inflammatory conditions of the jaw. RESULTS: The absolute risk at 3 years for any jaw toxicity was 0.70 events per 100 patients using bisphosphonates and 0.30 events per 100 patients not using such drugs (2-sided log rank test, p = 0.08). In multivariable survival analyses (Cox proportional hazards regression) adjusting for potential confounders, intravenous bisphosphonate use was not significantly associated with diagnoses or procedures suggestive of osteonecrosis of the jaw (p = 0.24). CONCLUSIONS: Patients with osteoporosis who are treated with intravenous bisphosphonates do not appear to have a statistically significant increase in the incidence of osteonecrosis of the jaw over 3 years compared with those who do not receive such treatment. Future studies will further contribute to our understanding of the bisphosphonate risk profile, thereby allowing patients and physicians to more rigorously assess the risk-benefit ratio of this treatment across different clinical scenarios.

A matched cohort study of the risk of cancer in users of becaplermin.

BACKGROUND: Becaplermin is recombinant human platelet-derived growth factor for topical administration that might plausibly be related to cancer risk. Extended follow-up of patients from clinical trials of becaplermin compared with placebo identified a relative risk of cancer of 2.8 (95% confidence interval [CI], 0.6-12.8). The authors aimed to further investigate any association between becaplermin use and the occurrence of cancer by following a large cohort of patients in a clinical practice setting. METHODS: In a cohort of insured people, becaplermin initiators were matched to similar people who did not initiate becaplermin and were followed for up to 6 years for cancer incidence (up to 9 years for cancer mortality). Cancer incidence was identified from health insurance claims and validated by review of medical records. Cancer mortality was identified through linkage to the National Death Index. RESULTS: Among 1622 becaplermin initiators, there were 28 confirmed cancers and 9 cancer deaths, and among the 2809 matched comparators, there were 43 confirmed cancers and 16 cancer deaths. There was no increased risk of cancer with becaplermin (hazard ratio, 1.2; 95% CI, 0.7-1.9). Cancer mortality through 2003 was increased (rate ratio [RR] = 5.2; 95% CI, 1.7-17.6) among subjects with 3 or more dispensings. Additional follow-up through 2006 indicated no elevated cancer mortality risk overall (RR, 1.0; 95% CI, 0.5-2.3) and no statistically significant increase in the subgroup with more than 3 dispensings (RR, 2.4; 95% CI, 0.8-7.4). CONCLUSIONS: Becaplermin does not appear to increase the risk of cancer or cancer mortality.

Atrial fibrillation and stroke associated with intravenous bisphosphonate therapy in older patients with cancer.

PURPOSE: Recent studies have linked the use of intravenous and orally administered bisphosphonates with subsequent development of atrial fibrillation. Patients with cancer who receive intravenous bisphosphonate therapy may be at particular risk for this adverse event because they receive higher doses of these drugs than do patients treated for other indications. We examined the association of intravenous bisphosphonates with atrial fibrillation, all classifications of supraventricular tachycardia (SVT), and stroke among older patients with cancer. PATIENTS AND METHODS: Using Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked data, we identified older (≥ age 65 years) patients with cancer who were treated with intravenous infusions of bisphosphonates between January 1, 1995 and December 31, 2003. We then matched 13,714 bisphosphonate nonusers to 6,857 bisphosphonate users, at a 2:1 ratio, on cancer type, age, sex, presence of bone metastases, and SEER geographic region. Patients were observed until December 31, 2003 or until they lost coverage from Medicare Parts A and B; enrolled in a health maintenance organization; received a diagnosis of atrial fibrillation, any SVT, or stroke; or died. RESULTS: Receipt of intravenous bisphosphonates was modestly associated with an increased risk for atrial fibrillation (hazard ratio [HR] = 1.30; 95% CI, 1.18 to 1.43), all SVT (HR = 1.28; 95% CI, 1.19 to 1.38), and stroke (HR = 1.30; 95% CI, 1.09 to 1.54). The risk for all SVT increased 7% for each increase of five bisphosphonate dose equivalents (HR = 1.07; 95% CI, 1.02 to 1.12). CONCLUSION: Clinicians who treat patients with cancer who have received intravenous bisphosphonates should be aware of the possible cardiovascular adverse events associated with this treatment.

Intravenous bisphosphonate therapy and inflammatory conditions or surgery of the jaw: a population-based analysis.

BACKGROUND: Recent reports have identified an association between osteonecrosis of the jaw or facial bones and treatment with nitrogen-containing intravenous bisphosphonates. We investigated this association by use of data from the Surveillance, Epidemiology, and End Results (SEER) program linked to Medicare claims. METHODS: We identified 16,073 cancer patients who were diagnosed between January 1, 1986, and December 31, 2002, and were treated intravenously with the bisphosphonates pamidronate and/or zoledronic acid between January 1, 1995, and December 31, 2003. We matched 28,698 bisphosphonate nonusers, at a 2:1 ratio, to 14,349 bisphosphonate users on month and year of the first bisphosphonate administration received by users, cancer type, age, sex, risk factors for osteonecrosis (diabetes, alcoholism, cigarette smoking, obesity, hyperlipemia, pancreatitis, or chemotherapy with L-asparaginase), bone metastasis, and SEER program geographic region. Patients were followed until the study's end on December 31, 2003; loss of coverage from Medicare Parts A and B; or one of the following outcomes: a diagnosis of inflammatory conditions or osteomyelitis of the jaw, surgery on the facial bones, or death, whichever occurred first. RESULTS: Use of intravenous bisphosphonates was associated with an increased risk of jaw or facial bone surgery (hazard ratio [HR] = 3.15, 95% confidence interval [CI] = 1.86 to 5.32) and an increased risk of being diagnosed with inflammatory conditions or osteomyelitis of the jaw (HR = 11.48, 95% CI = 6.49 to 20.33), compared with nonuse. The absolute risk at 6 years for any jaw toxicity was 5.48 events per 100 patients using intravenous bisphosphonates and 0.30 events per 100 patients not using such drugs. The risk of each outcome increased as cumulative dose increased (e.g., for 4-8 infusions, HR for operations on the jaw and facial bones = 3.63, 95% CI = 0.77 to 17.08; for more than 21 infusions, HR = 9.18, 95% CI = 1.74 to 48.53). CONCLUSION: Users of intravenous bisphosphonates had an increased risk of inflammatory conditions, osteomyelitis, and surgical procedures of the jaw and facial bones. The increased risk may reflect an increased risk for osteonecrosis of the jaw.

Intakes of selected nutrients, foods, and phytochemicals and prostate cancer risk in western New York.

A number of epidemiological studies have suggested that diet may affect the etiology of prostate cancer, but few have investigated the impact of phytochemical intakes on this cancer. We conducted a case-control study of diet and prostate cancer in western New York involving 433 men with primary, histologically confirmed prostate cancer and 538 population-based controls, frequency matched to cases on age and county of residence. Diet was assessed with a detailed food-frequency questionnaire. We calculated daily intakes of nutrients and the phytochemicals beta-sitosterol, campesterol, stigmasterol, total phytosterols, total lignan precursors, quercetin, and kaempferol based on published food composition data. Odds ratios (ORs) and 95% confidence intervals (CIs) describing the association of prostate cancer risk with selected nutrients, phytochemicals, and food groups were estimated with unconditional logistic regression. Compared with men in the lowest quartile of intake, reduced risks were observed for men in the highest quartile of intake of vitamin C (OR = 0.49; 95% CI = 0.33-0.74), beta-carotene (OR = 0.53; 95% CI = 0.36-0.79), alpha-carotene (OR = 0.67; 95% CI = 0.47-0.97), lutein (OR = 0.55; 95% CI = 0.37-0.81), lycopene (OR = 0.62; 95% CI = 0.42-0.92), total lignan precursors (OR = 0.66; 95% CI = 0.47-0.94), quercetin (OR = 0.64; 95% CI = 0.44-0.92), and total vegetables (OR = 0.53; 95% CI = 0.36-0.79), but weak increased risks were observed for snacks and sweets (OR = 1.46; 95% CI = 0.95-2.23). Estimates associated with nutrients and phytochemicals were attenuated after adjustment for total vegetable intake. Nevertheless, our results support the hypothesis that a phytochemical-rich, plant-based diet is of importance in reducing risks of hormone-related neoplasms.

Nested case-control study of external ionizing radiation dose and mortality from dementia within a pooled cohort of female nuclear weapons workers.

BACKGROUND: A prior investigation of this cohort of female nuclear workers found increased deaths from mental disorders, including dementia. The present study estimates the effect of workplace exposures to ionizing radiations and other hazards on mortality from dementia. METHODS: A nested case-control study within a pooled cohort of 67,976 female nuclear workers compared 91 cases of death from dementia with 910 controls. Adjusted odds ratios (ORs) were employed to estimate the effects of maximum annual and total lifetime radiation doses on the occurrence of dementia in 168 monitored workers. RESULTS: Both maximum annual (OR = 2.11, 95% confidence interval (CI) = 0.98, 4.40) and total lifetime radiation doses (OR = 2.09, 95% CI = 1.02, 4.29) were associated with death from dementia. Significant dose-response trends were present for both exposures. CONCLUSIONS: Occupational exposure to ionizing radiation (IR) may be associated with increased risk of death from dementia in female workers. Since these findings are based on a small number of cases, replication with a larger case sample should be pursued.