Risk of Ischemic Stroke Associated with Calcium Supplements and Interaction with Oral Bisphosphonates: A Nested Case-Control Study.

Conflicting results about the association of calcium supplements (CS) with ischemic stroke (IS) have been reported. We tested this hypothesis by differentiating between CS alone (CaM) and CS with vitamin D (CaD) and between cardioembolic and non-cardioembolic IS. We examined the potential interaction with oral bisphosphonates (oBs). A nested case-control study was carried out. We identified incident IS cases aged 40-90 and randomly sampled five controls per case matched by age, sex, and index date. Current users were compared to non-users. An adjusted odds ratios (AOR) and 95% CI were computed through conditional logistic regression. Only new users were considered. We included 13,267 cases (4400 cardioembolic, 8867 non-cardioembolic) and 61,378 controls (20,147 and 41,231, respectively). CaM use was associated with an increased risk of cardioembolic IS (AOR = 1.88; 95% CI: 1.21-2.90) in a duration-dependent manner, while it showed no association with non-cardioembolic IS (AOR = 1.05; 95% CI: 0.74-1.50); its combination with oBs increased the risk of cardioembolic IS considerably (AOR = 2.54; 95% CI: 1.28-5.04), showing no effect on non-cardioembolic. CaD use was not associated with either cardioembolic (AOR = 1.08; 95% CI: 0.88-1.31) or non-cardioembolic IS (AOR = 0.98; 95% CI: 0.84-1.13) but showed a small association with cardioembolic IS when combined with oBs (AOR = 1.35; 95% CI: 1.03-1.76). The results support the hypothesis that CS increases the risk of cardioembolic IS, primarily when used concomitantly with oBs.

Association of oral bisphosphonates with cardioembolic ischemic stroke: a nested case-control study.

Background: Bisphosphonates have been reported to increase the risk of atrial fibrillation. Therefore, it is conceivable that they may increase the risk of cardioembolic ischemic stroke (IS). However, most epidemiological studies carried out thus far have not shown an increased risk of IS, though none separated by the main pathophysiologic IS subtype (cardioembolic and non-cardioembolic) which may be crucial. In this study, we tested the hypothesis that the use of oral bisphosphonates increases specifically the risk of cardioembolic IS, and explored the effect of treatment duration, as well as the potential interaction between oral bisphosphonates and calcium supplements and anticoagulants. Methods: We performed a case-control study nested in a cohort of patients aged 40-99 years, using the Spanish primary healthcare database BIFAP, over the period 2002-2015. Incident cases of IS were identified and classified as cardioembolic or non-cardioembolic. Five controls per case were randomly selected, matched for age, sex, and index date (first recording of IS) using an incidence-density sampling. The association of IS (overall and by subtype) with the use of oral bisphosphonates within the last year before index date was assessed by computing the adjusted odds ratios (AOR) and their 95% CI using a conditional logistic regression. Only initiators of oral bisphosphonates were considered. Results: A total of 13,781 incident cases of IS and 65,909 controls were included. The mean age was 74.5 (SD ± 12.4) years and 51.6% were male. Among cases, 3.15% were current users of oral bisphosphonates, while among controls they were 2.62%, yielding an AOR of 1.15 (95% CI:1.01-1.30). Of all cases, 4,568 (33.1%) were classified as cardioembolic IS (matched with 21,697 controls) and 9,213 (66.9%) as non-cardioembolic IS (matched with 44,212 controls) yielding an AOR of 1.35 (95% CI:1.10-1.66) and 1.03 (95% CI: 0.88-1.21), respectively. The association with cardioembolic IS was clearly duration-dependent (AOR≤1 year = 1.10; 95% CI:0.82-1.49; AOR>1-3 years = 1.41; 95% CI:1.01-1.97; AOR>3 years = 1.81; 95% CI:1.25-2.62; p for trend = 0.001) and completely blunted by anticoagulants, even in long-term users (AOR>1 year = 0.59; 0.30-1.16). An interaction between oral bisphosphonates and calcium supplements was suggested. Conclusion: The use of oral bisphosphonates increases specifically the odds of cardioembolic IS, in a duration-dependent manner, while leaves materially unaffected the odds of non-cardioembolic IS.

Influenza Vaccination and Risk of Ischemic Stroke: A Population-Based Case-Control Study.

BACKGROUND AND OBJECTIVES: To assess the relationship between influenza vaccination in the general population and risk of a first ischemic stroke (IS) during pre-epidemic, epidemic and post-epidemic periods. METHODS: A nested case-control study was carried out in a Spanish primary care database over 2001-2015. Subjects aged 40-99 years with at-least 1-year registry and no history of stroke or cancer were selected to conform the source cohort, from which incident IS cases were identified and classified as cardioembolic or non-cardioembolic. Five controls per case were randomly selected, individually matched with cases for exact age, sex and date of stroke diagnosis (index date). A patient was considered vaccinated when he/she had a recorded influenza vaccination at least 14 days before the index date within the same season. Adjusted odds ratios (AOR) and their respective 95% confidence intervals (CI) were computed through a conditional logistic regression. Pneumococcal vaccination was used as a negative control. RESULTS: From a cohort of 3,757,621 patients, we selected 14,322 incident IS cases (9,542 non-cardioembolic and 4,780 cardioembolic) and 71,610 matched controls. Of them, 41.4% and 40.5%, respectively, were vaccinated yielding a crude OR of 1.05(95%CI:1.01-1.10). Vaccinated subjects presented a higher prevalence of vascular risk factors, diseases and comedication than non-vaccinated and, after full adjustment, the association of influenza vaccination with IS yielded an AOR of 0.88(95%CI:0.84-0.92) was found, appearing early (AOR15-30 days=0.79;95%CI:0.69-0.92) and slightly declining over time (AOR>150 days=0.92;95%CI:0.87-0.98). A reduced risk of similar magnitude was observed with both types of IS, in the three epidemic periods and in all subgroups analyzed (men, women, subjects below and over 65 years of age, and subjects with intermediate and high vascular risk). By contrast, pneumococcal vaccination was not associated with a reduced risk of IS (AOR=1.08;95%CI:1.04-1.13). DISCUSSION: Results are compatible with a moderate protective effect of influenza vaccine on IS appearing early after vaccination. The finding that a reduced risk was also observed in pre-epidemic periods suggests that either the "protection" is not totally linked to prevention of influenza infection, or it may be partly explained by unmeasured confounding factors.

Risk of ischaemic stroke among new users of glucosamine and chondroitin sulphate: a nested case-control study.

Background: Several studies have reported that the use of chondroitin sulphate (CS) and glucosamine may reduce the risk of acute myocardial infarction. Although it is thought that this potential benefit could be extended to ischaemic stroke (IS), the evidence is scarce. Objective: To test the hypothesis that the use of prescription glucosamine or CS reduces the risk of IS. Design: Case-control study nested in an open cohort. Methods: Patients aged 40-99 years registered in a Spanish primary healthcare database (BIFAP) during the 2002-2015 study period. From this cohort, we identified incident cases of IS, applying a case-finding algorithm and specific validation procedures, and randomly sampled five controls per case, individually matched with cases by exact age, gender and index date. Adjusted odds ratios (AORs) and 95% confidence interval (CI) were computed through a conditional logistic regression. Only new users of glucosamine or CS were considered. Results: A total of 13,952 incident cases of IS and 69,199 controls were included. Of them, 106 cases (0.76%) and 803 controls (1.16%) were current users of glucosamine or CS at index date, yielding an AOR of 0.66 (95% CI: 0.54-0.82) (for glucosamine, AOR: 0.55; 95% CI: 0.39-0.77; and for CS, AOR: 0.77; 95% CI: 0.60-0.99). The reduced risk among current users was observed in both sexes (men, AOR: 0.69; 95% CI: 0.49-0.98; women, AOR: 0.65; 95% CI: 0.50-0.85), in individuals above and below 70 years of age (AOR: 0.69; 95% CI: 0.53-0.89 and AOR: 0.59; 95% CI: 0.41-0.85, respectively), in individuals with vascular risk factors (AOR: 0.53; 95% CI: 0.39-0.74) and among current/recent users of nonsteroidal anti-inflammatory drugs (NSAIDs) (AOR: 0.71; 95% CI: 0.55-0.92). Regarding duration, the reduced risk was observed in short-term users (<365 days, AOR: 0.61; 95% CI: 0.48-0.78) while faded and became nonsignificant in long-term users (>364 days AOR: 0.86; 95% CI: 0.57-1.31). Conclusions: Our results support a protective effect of prescription CS and glucosamine in IS, which was observed even in patients at vascular risk. Mini abstract: Our aim was to analyse whether the use of glucosamine or chondroitin sulphate (CS) reduces the risk of ischaemic stroke (IS). We detected a significant decrease.

Selective Serotonin Reuptake Inhibitors and Risk of Noncardioembolic Ischemic Stroke: A Nested Case-Control Study.

BACKGROUND: Multiple studies have reported that the use of selective serotonin reuptake inhibitors (SSRIs) is associated with an increased risk of ischemic stroke; however, this finding may be the result of a confounding by indication. We examined the association using different approaches to minimize such potential bias. METHODS: A nested case-control study was carried out in a Spanish primary health-care database over the study period 2001 to 2015. Cases were patients sustaining an ischemic stroke with no sign of cardioembolic or unusual cause. For each case, up to 5 matched controls (for exact age, sex, and index date) were randomly selected. Antidepressants were divided in 6 pharmacological subgroups according to their mechanism of action. The current use of SSRIs (use within a 30-day window before index date) was compared with nonuse, past use (beyond 365 days) and current use of other antidepressants through a conditional logistic regression model to obtain adjusted odds ratios and 95% CI. Only initiators of SSRIs and other antidepressants were considered. RESULTS: A total of 8296 cases and 37 272 matched controls were included. Of them, 255 (3.07%) were current users of SSRIs among cases and 834 (2.24%) among controls, yielding an adjusted odds ratio of 1.14 (95% CI, 0.97-1.34) as compared with nonusers, 0.94 (95% CI, 0.77-1.13) as compared with past-users and 0.74 (95% CI, 0.58-0.93) as compared with current users of other antidepressants. No relevant differences were found by duration (≤1, >1 year), sex, age (<70, ≥70 years old) and background vascular risk. CONCLUSIONS: The use of SSRIs was not associated with an increased risk of noncardioembolic ischemic stroke. On the contrary, as compared with other antidepressants, SSRIs appeared to be protective.

Long-Term Anticoagulation in Secondary Ischemic Stroke Prevention: The Prospective Multicenter RESTAIC Registry.

Background and Objective: Oral anticoagulation (OAC) for secondary stroke prevention is recommended in atrial fibrillation (AF) and other sources of cardioembolic stroke. Our objectives were to explore the differences in ischemic and hemorrhagic events when using OAC for secondary stroke prevention according to the type of anticoagulant treatment and to analyze the number and reasons for OAC switches during long-term follow-up. Methods: Ischemic stroke (IS) patients who were discharged on OAC for secondary stroke prevention from January 2014 to October 2017 were recruited in a prospective, multicenter, hospital-based registry. Follow-up at 3 months was scheduled at the outpatient clinic with subsequent annual phone interviews for 3 years. Patients were classified into three study groups according to OAC at discharge: Vitamin K antagonist (VKA), Factor Xa inhibitor (FXa), or direct thrombin inhibitor (DTI). We compared stroke recurrences, intracranial hemorrhage, major bleeding, and all-cause mortality during the follow-up. We recorded any switches in OAC and the main reasons for the change. Results: A total of 241 patients were included. An anticoagulant was indicated in the presence of a source of cardioembolic stroke in 240 patients (99.6%) and lupus plus antiphospholipid syndrome in one patient. Up to 86 patients (35.6%) were on OAC before the index stroke; in 71 (82.5%) of them, this was VKA. At hospital discharge, 105 were treated with FXa (43.8%), 96 with VKA (39.6%), and 40 with DTI (16.6%). The cumulative incidences at 3 years were 17% for stroke recurrence, 1.6% for intracranial hemorrhage, 4.9% for major hemorrhage, and 22.8% for all-cause mortality, with no differences among the OAC groups in any outcomes. During the follow-up, 40 OAC switches were recorded (63% of them to FXa), mostly due to stroke recurrence. Conclusion: Long-term OAC in secondary stroke prevention is associated with a lower frequency of bleeding complications than stroke recurrences. No differences between anticoagulant drugs were found in any of the analyzed outcomes. The main cause for OAC switch during follow-up was stroke recurrence.

Primer caso descrito de parálisis aislada, completa y fluctuante del III nervio craneal como forma de inicio de un mieloma múltiple / First case described of isolated, complete and fluctuating cranial nerve III palsy heralding multiple myeloma

Introducción. El mieloma múltiple es la neoplasia de células plasmáticas más frecuente. Al ser incurable, el tratamiento persigue obtener el mayor tiempo de supervivencia libre de clínica. Constituye una causa extremadamente rara de afectación de los nervios craneales y es producido habitualmente por un plasmocitoma intracraneal. Presentamos un caso de mieloma múltiple, que asociaba un plasmocitoma intracraneal y que comenzó clínicamente con parálisis aislada, completa y fluctuante del III nervio craneal. Caso clínico. Mujer de 63 años que acudió a urgencias por presentar un cuadro clínico oscilante, consistente en diplopía binocular horizontal y, posteriormente, cefalea. La exploración neurooftalmológica reveló una parálisis completa del III nervio craneal derecho. Se solicitó una tomografía axial computarizada craneal urgente, que reveló múltiples lesiones osteolíticas diploicas, asociando una de ellas componente de partes blandas en la hendidura esfenoidal derecha. La paciente fue ingresada, y se le diagnosticó posteriormente un mieloma múltiple IgA-k. Tras recibir inducción quimioterápica y ser sometida a un trasplante autólogo de progenitores hematopoyéticos, alcanzó la remisión completa. Conclusiones. El mieloma múltiple es un trastorno raro de los nervios craneales, una causa muy infrecuente de parálisis aislada y completa del III nervio craneal y menos aún fluctuante, y no se ha encontrado ningún caso publicado con este inicio clínico. Tener en cuenta las posibles manifestaciones neurooftalmológicas del mieloma múltiple puede contribuir a un diagnóstico precoz y a una incidencia positiva sobre el curso de esta enfermedad (AU)

Introduction. Multiple myeloma is the most common plasma-cell malignancy. To be incurable, treatment aims to obtain the longest non-clinical survival time. Cranial nerve palsy in multiple myeloma is extremely rare and is usually due to an intracranial plasmacytoma. We present a multiple myeloma case, with an intracranial plasmacytoma, which debuted clinically with isolated, complete and fluctuating cranial nerve III palsy. Case report. A 63-year-old woman presented an oscillating clinical picture, consisting of horizontal binocular diplopia and later, headache. The neuro-ophthalmologic examination revealed a complete cranial nerve III palsy of the right eye. An urgent cranial CT-scan was requested. It showed multiple diploic osteolytic lesions, associating soft-parts component in the right superior orbital fissure. The patient was admitted, being diagnosed subsequently of IgA-k multiple myeloma. After receiving induction-chemotherapy and undergoing autologous stem cell transplantation, she achieved full remission. Conclusions. Multiple myeloma is a rare cranial nerves disorder, very uncommon cause of cranial nerve III full isolated paralysis and even less fluctuating, not having found any case published with this clinical onset. Awareness of possible multiple myeloma neuro-ophthalmic manifestations may bring about an early diagnosis and a positive impact on the disease course (AU)

[First case described of isolated, complete and fluctuating cranial nerve III palsy heralding multiple myeloma]. / Primer caso descrito de parálisis aislada, completa y fluctuante del III nervio craneal como forma de inicio de un mieloma múltiple.

INTRODUCTION: Multiple myeloma is the most common plasma-cell malignancy. To be incurable, treatment aims to obtain the longest non-clinical survival time. Cranial nerve palsy in multiple myeloma is extremely rare and is usually due to an intracranial plasmacytoma. We present a multiple myeloma case, with an intracranial plasmacytoma, which debuted clinically with isolated, complete and fluctuating cranial nerve III palsy. CASE REPORT: A 63-year-old woman presented an oscillating clinical picture, consisting of horizontal binocular diplopia and later, headache. The neuro-ophthalmologic examination revealed a complete cranial nerve III palsy of the right eye. An urgent cranial CT-scan was requested. It showed multiple diploic osteolytic lesions, associating soft-parts component in the right superior orbital fissure. The patient was admitted, being diagnosed subsequently of IgA-kappa multiple myeloma. After receiving induction-chemotherapy and undergoing autologous stem cell transplantation, she achieved full remission. CONCLUSIONS: Multiple myeloma is a rare cranial nerves disorder, very uncommon cause of cranial nerve III full isolated paralysis and even less fluctuating, not having found any case published with this clinical onset. Awareness of possible multiple myeloma neuro-ophthalmic manifestations may bring about an early diagnosis and a positive impact on the disease course.

TITLE: Primer caso descrito de paralisis aislada, completa y fluctuante del III nervio craneal como forma de inicio de un mieloma multiple.Introduccion. El mieloma multiple es la neoplasia de celulas plasmaticas mas frecuente. Al ser incurable, el tratamiento persigue obtener el mayor tiempo de supervivencia libre de clinica. Constituye una causa extremadamente rara de afectacion de los nervios craneales y es producido habitualmente por un plasmocitoma intracraneal. Presentamos un caso de mieloma multiple, que asociaba un plasmocitoma intracraneal y que comenzo clinicamente con paralisis aislada, completa y fluctuante del III nervio craneal. Caso clinico. Mujer de 63 años que acudio a urgencias por presentar un cuadro clinico oscilante, consistente en diplopia binocular horizontal y, posteriormente, cefalea. La exploracion neurooftalmologica revelo una paralisis completa del III nervio craneal derecho. Se solicito una tomografia axial computarizada craneal urgente, que revelo multiples lesiones osteoliticas diploicas, asociando una de ellas componente de partes blandas en la hendidura esfenoidal derecha. La paciente fue ingresada, y se le diagnostico posteriormente un mieloma multiple IgA-kappa. Tras recibir induccion quimioterapica y ser sometida a un trasplante autologo de progenitores hematopoyeticos, alcanzo la remision completa. Conclusiones. El mieloma multiple es un trastorno raro de los nervios craneales, una causa muy infrecuente de paralisis aislada y completa del III nervio craneal y menos aun fluctuante, y no se ha encontrado ningun caso publicado con este inicio clinico. Tener en cuenta las posibles manifestaciones neurooftalmologicas del mieloma multiple puede contribuir a un diagnostico precoz y a una incidencia positiva sobre el curso de esta enfermedad.