Thomas Delate

Risk of Heart Failure in Breast Cancer Patients After Anthracycline and Trastuzumab Treatment: A Retrospective Cohort Study

Background Clinical trials demonstrated that women treated for breast cancer with anthracycline or trastuzumab are at increased risk for heart failure and/or cardiomyopathy (HF/CM), but the generalizability of these findings is unknown. We estimated real-world adjuvant anthracycline and trastuzumab use and their associations with incident HF/CM. Methods We conducted a population-based, retrospective cohort study of 12 500 women diagnosed with incident, invasive breast cancer from January 1, 1999 through December 31, 2007, at eight integrated Cancer Research Network health systems. Using administrative procedure and pharmacy codes, we identified anthracycline, trastuzumab, and other chemotherapy use. We identified incident HF/CM following chemotherapy initiation and assessed risk of HF/CM with time-varying chemotherapy exposures vs no chemotherapy. Multivariable Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) with adjustment for age at diagnosis, stage, Cancer Research Network site, year of diagnosis, radiation therapy, and comorbidities. Results Among 12 500 women (mean age = 60 years, range = 22–99 years), 29.6% received anthracycline alone, 0.9% received trastuzumab alone, 3.5% received anthracycline plus trastuzumab, 19.5% received other chemotherapy, and 46.5% received no chemotherapy. Anthracycline and trastuzumab recipients were younger, with fewer comorbidities than recipients of other chemotherapy or none. Compared with no chemotherapy, the risk of HF/CM was higher in patients treated with anthracycline alone (adjusted HR = 1.40, 95% CI = 1.11 to 1.76), although the increased risk was similar to other chemotherapy (adjusted HR = 1.49, 95% CI = 1.25 to 1.77); the risk was highly increased in patients treated with trastuzumab alone (adjusted HR = 4.12, 95% CI = 2.30 to 7.42) or anthracycline plus trastuzumab (adjusted HR = 7.19, 95% CI = 5.00 to 10.35). Conclusions Anthracycline and trastuzumab were primarily used in younger, healthier women and associated with increased HF/CM risk compared with no chemotherapy. This population-based observational study complements findings from clinical trials on cancer treatment safety.

Outcomes and predictors of very stable INR control during chronic anticoagulation therapy

For patients on warfarin therapy, an international normalized ratio (INR) recall interval not exceeding 4 weeks has traditionally been recommended. Less frequent INR monitoring may be feasible in stable patients. We sought to identify patients with stable INRs (defined as having INR values exclusively within the INR range) and comparator patients (defined as at least one INR outside the INR range) in a retrospective, longitudinal cohort study. Occurrences of thromboembolism, bleeding, and death were compared between groups. Multivariate logistic regression models were used to identify independent predictors of stable INR control. There were 2504 stable and 3569 comparator patients. The combined rates of bleeding and thromboembolism were significantly lower in stable patients. Independent predictors of stable INR control were age older than 70 years and the absence of comorbid heart failure and diabetes. Stable patients were significantly less likely to have target INR of 3.0 or higher or chronic diseases. We hypothesize that many patients demonstrating stable INR control could be safely treated with INR recall intervals greater than the traditional 4 weeks.

Twelve-month outcomes and predictors of very stable INR control in prevalent warfarin users

Summary.  Background:  For patients on warfarin therapy an international normalized ratio (INR) recall interval not exceeding 4 weeks has traditionally been recommended. For patients whose INR values are nearly always therapeutic, less frequent INR monitoring may be feasible.

Incidence and predictors of bleeding or thrombosis after polypectomy in patients receiving and not receiving anticoagulation therapy

Summary.  Background and aims: To assess the effect of warfarin anticoagulation therapy (AC) on the incidence of colon bleeding after elective colonoscopy with polypectomy and to identify independent predictors of post‐polypectomy colon bleeding. Methods: This was a retrospective cohort analysis. Patients interrupting warfarin AC therapy for polypectomy (AC group) were matched on age (± 3 years) with up to two patients who underwent polypectomy but were not receiving AC (non‐AC group). Data were extracted from electronic medical, pharmacy and laboratory claims and records and manual medical chart review. Incidence rates of colon bleeding requiring hospitalization, other gastrointestinal bleeding, thrombosis and death in the 30 days post‐polypectomy were compared between groups. Multivariate regression techniques were used to identify independent predictors of post‐polypectomy colon bleeding. Results: A total of 425 AC group patients were matched to 800 non‐AC group patients. Post‐polypectomy colon bleeding occurred more often in AC group patients (2.6% vs. 0.2%, P = 0.005). There were no differences in the rates of other outcomes (P > 0.05). Independent predictors of colon bleeding included AC group status [adjusted odds ratio (AOR) = 11.6; 95% confidence interval (CI) = 2.3–57.3], number of polyps removed (AOR = 1.2; 95% CI = 1.1–1.4) and male gender (AOR = 9.2, 95% CI = 1.1–74.9). Conclusions: The incidence of post‐polypectomy colon bleeding was higher in patients receiving AC even although warfarin was interrupted for the procedure. Independent predictors of colon bleeding were identified as: receiving AC, removal of multiple polyps and male gender. Our findings suggest that additional methods to reduce the likelihood of post‐polypectomy colon bleeding in AC patients should be investigated.

Outcomes Associated With Combined Antiplatelet and Anticoagulant Therapy

BACKGROUND The use of antiplatelet therapy in combination with oral anticoagulants remains controversial. The objective of this study was to estimate and compare the incidence of adverse and coronary event rates between patients receiving warfarin monotherapy or warfarin and antiplatelet combination therapy. METHODS This was a retrospective, longitudinal, pharmacoepidemiologic analysis. Adult patients receiving warfarin managed by an anticoagulation service who had documented the use of antiplatelet agents (eg, aspirin, clopidogrel, and/or dipyridamole) [ie, the combination-therapy cohort] or their nonuse (ie, the monotherapy cohort) were identified as of September 30, 2005. Utilizing integrated, electronic medical records, anticoagulation-related adverse events (eg, death, hemorrhage, or thrombosis) and coronary events were identified during a 6-month follow-up period (October 2005 through March 2006). The proportions of events were compared between cohorts. Independent associations between the cohorts and the outcomes were assessed with adjustment for potential confounding factors. RESULTS Data from 2,560 patients in the monotherapy cohort and 1,623 patients in the combination-therapy cohort were analyzed. Patients in the combination-therapy cohort were more likely to have had anticoagulation-related hemorrhages (4.2% vs 2.0%, respectively; unadjusted p < 0.001) and coronary events (0.9% vs 0.3%, respectively; p = 0.009), but not death (0.1% vs 0.2%, respectively; unadjusted p = 0.186) or thrombotic events (0.3% vs 0.4%, respectively; unadjusted p = 0.812). With adjustment, combined warfarin and antiplatelet use was independently associated with hemorrhagic events (odds ratio [OR], 2.75; 95% confidence interval [CI], 1.44 to 5.28), but not with coronary events (OR, 0.99; 95% CI, 0.37 to 2.62). CONCLUSIONS At the population level, the hemorrhagic risk associated with warfarin therapy combined with antiplatelet therapy appears to outweigh the benefits. These findings suggest that clinicians should carefully consider the risks and benefits when recommending combined antiplatelet therapy for patients receiving warfarin who do not meet the evidence-based criteria for such therapy.

Clinical Outcomes of a Home-Based Medication Reconciliation Program After Discharge from a Skilled Nursing Facility

Study Objective. To assess the impact of a pilot pharmacist‐managed medication reconciliation program on mortality and use of health care services in patients discharged to home from a skilled nursing facility (SNF).

Bleeding, Recurrent Venous Thromboembolism, and Mortality Risks During Warfarin Interruption for Invasive Procedures

IMPORTANCE The risk of bleeding and recurrent venous thromboembolism (VTE) among patients receiving long-term warfarin sodium therapy for secondary VTE prevention who require temporary interruption of anticoagulant therapy for surgery or invasive diagnostic procedures has not been adequately described. OBJECTIVE To describe the rates of clinically relevant bleeding and recurrent VTE among patients in whom warfarin therapy is interrupted for invasive procedures and compare these rates among patients who did and did not receive bridge therapy. DESIGN, SETTING, AND PARTICIPANTS A retrospective cohort study was conducted at Kaiser Permanente Colorado, an integrated health care delivery system. Patients in whom warfarin therapy was interrupted for invasive diagnostic or surgical procedures between January 1, 2006, and March 31, 2012, were identified via queries of administrative data sets. A total of 1812 procedures in 1178 patients met inclusion criteria. Data on outcomes and exposures were collected between June 1, 2005, and April 30, 2012. EXPOSURES Use of bridge therapy vs no bridge therapy during warfarin interruption. MAIN OUTCOMES AND MEASURES Thirty-day clinically relevant bleeding, recurrent VTE, and all-cause mortality. Outcomes were verified via manual review of medical records. RESULTS Among the 1178 patients, the mean (SD) age was 66.1 (12.7) years, 830 procedures (45.8%) were in men, and the most common indication for warfarin therapy was deep vein thrombosis (56.3%). Most patients were considered to be at low risk for VTE recurrence at the time of warfarin interruption (1431 procedures [79.0%]) according to the consensus guidelines of the American College of Chest Physicians. Clinically relevant bleeding within 30 days after the procedure in the bridge therapy and non-bridge therapy groups occurred in 15 patients (2.7%) and 2 patients (0.2%), respectively (hazard ratio, 17.2; 95% CI, 3.9-75.1). There was no significant difference in the rate of recurrent VTE between the bridge and non-bridge therapy groups (0 vs 3; P = .56). No deaths occurred in either group. CONCLUSIONS AND RELEVANCE Bridge therapy was associated with an increased risk of bleeding during warfarin therapy interruption for invasive procedures in patients receiving treatment for a history of VTE and is likely unnecessary for most of these patients. Further research is needed to identify patient- and procedure-related characteristics associated with a high risk of perioperative VTE recurrence during warfarin therapy interruption.

Thromboembolic Consequences of Subtherapeutic Anticoagulation in Patients Stabilized on Warfarin Therapy: The Low INR Study

Study Objective. To quantify the absolute risk of thromboembolism associated with a significant subtherapeutic international normalized ratio (INR) in patients with previously stable anticoagulation while receiving warfarin.

Outpatient Use of Low Molecular Weight Heparin Monotherapy for First-Line Treatment of Venous Thromboembolism in Advanced Cancer

BACKGROUND Evidence-based treatment guidelines recommend low molecular weight heparin (LMWH) monotherapy for cancer-associated venous thromboembolism (VTE). This analysis assessed the first-line treatment strategies for VTE in patients with advanced solid tumors. METHODS Using administrative data from advanced lung, prostate, colon, or breast cancer patients diagnosed between January 2000 and December 2007 at four HMOs with integrated delivery systems, patients with an inpatient or outpatient VTE diagnosed within 2 years after cancer diagnosis and an outpatient purchase of warfarin, LMWH, and/or fondaparinux anticoagulant within 7 days of the VTE diagnosis were identified. First-line outpatient VTE pharmacological treatment and factors independently associated with receipt/non-receipt of LMWH monotherapy were assessed. RESULTS Overall, 25% of the 1,089 eligible patients received LMWH monotherapy as primary VTE treatment. The percentage increased steadily over time from 18% among patients diagnosed in 2000 to 31% among those diagnosed in 2007. Factors associated with LMWH monotherapy included VTE diagnosis year, chemotherapy within 60 days prior to VTE diagnosis, history of VTE prior to cancer diagnosis, and invasive surgery in the 90 days following VTE diagnosis. Colorectal and prostate cancer patients versus lung cancer patients and stage III versus stage IV patients were less likely to be treated with LMWH monotherapy. CONCLUSIONS Adoption of LMWH monotherapy as initial treatment for cancer-associated VTE was low but increased steadily over the study period. Future studies should explore reasons underlying the underutilization of this preferred evidence-based treatment as well as the comparative effectiveness of LMWH versus warfarin-based anticoagulation in real-world cancer patients with VTE.

Patterns and Predictors of First-line Chemotherapy Use among Adults with Advanced Non-small Cell Lung Cancer in the Cancer Research Network

BACKGROUND Relatively low rates of chemotherapy receipt have been observed in older patients diagnosed with advanced non-small cell lung cancer (NSCLC) in SEER-Medicare-based studies. However, little is known about variation in first-line NSCLC chemotherapy use in younger patients, health maintenance organization (HMO)-based settings, and for high-cost, novel agents, such as bevacizumab and erlotinib. METHODS A cohort of 6614 stage IIIB/IV NSCLC patients aged ≥ 21 years diagnosed between 2000 and 2007 was identified at four HMOs that participate in the Cancer Research Network (CRN). Demographic, comorbidity, tumor characteristics, and chemotherapy treatment data were included in logistic regression models to identify factors associated with chemotherapy receipt and tests of association examined secular and age-specific variation in first-line chemotherapy regimens. RESULTS Within 120 days of diagnosis, 3612 (55%) patients received chemotherapy; increasing from 52% of patients diagnosed in 2000 to 59% in 2007 (p<0.001). Receipt was significantly higher for patients aged <65 years (64% versus 46% in ≥ 65) and was inversely related to stage and comorbidites (all p<0.001). Carboplatin and paclitaxel were received most frequently. Erlotinib and bevacizumab use in the later years of the study was associated with a significant change in distributions of first-line chemotherapies (p<0.001). CONCLUSIONS For patients alive 30 days post diagnosis, chemotherapy use was higher in the aged population (>65 years) than previously published estimates, and higher still among younger patients. Chemotherapy use increased over the observation period, and the mix of first-line therapies used changed substantially over time. Of note, novel, high cost treatments were used in first-line therapy prior to FDA approval, increasing significantly throughout the study period. These findings demonstrate the utility of HMO CRN data to augment SEER-Medicare to conduct comparative effectiveness research related to chemotherapy use and the use of specific agents, especially among younger patients.