2 Minute Medicine Rewind November 9, 2020

Association between antipsychotic use and acute ischemic heart disease in women but not in men: a retrospective cohort study of over one million primary care patients

1. There was a moderate association found between antipsychotic use and acute ischemic heart disease found in women, but not men.

Evidence Rating Level: 2 (Good)

The use of antipsychotic medications is increasing worldwide and is not limited to treating indications such as psychotic and bipolar disorder; up to 60% of prescriptions are written for off-label use treatment of anxiety, depression, dementia, sleep, and personality disorders. Studies have shown that metabolic abnormalities associated with long-term use of antipsychotics, such as weight gain, glucose intolerance, and dyslipidemia, lead to an increased risk of diabetes, cardiovascular disease, and mortality in this population. Growing evidence supports that there are differences in how women and men develop cardiovascular diseases, as well as in prevalence rates of risk factors (sedentary lifestyle, alcohol and tobacco use). However, sex difference in the association between antipsychotic use and ischemic heart disease (IHD) is poorly studied. In this retrospective cohort study, health records from 1 043 262 patients in the Hong Kong primary care population over 45 years of age were examined. 17 780 (1.7%) were prescribed antipsychotics within the last 12 months and 8 324 (0.8%) developed IHD. A mixed-effects Cox model was used to examine hazard ratios of acute hospitalization secondary to IHD comparing patients on antipsychotics and those without, while adjusting for confounders such as baseline morbidities, tobacco abuse, antidepressant and statin prescriptions. Antipsychotics were associated with an increased hazard rate of acute IHD among women (HR 1.32, 95% CI 1.05-1.67) but not among men. This result was further supported by a sex-combined model, with a likelihood ratio test suggesting significant interaction between antipsychotic use and sex (chi square = 4.72, p=0.030). Moreover, the sensitivity analysis showed that, after replicating the main analysis and omitting one out of sixteen antipsychotics each time, the hazard ratios for antipsychotic use among women stayed similar except in the analysis where haloperidol was omitted (HR: 1.23, 95% CI 0.96-1.60). This suggests use of haloperidol may underlie this sex difference. While this study showed a moderate association specific to females in antipsychotic use and IHD, further studies should investigate a potential dose-effect relationship while implementing randomization procedures to isolate the independent effect of the antipsychotics.


Efficacy and safety of short-term therapy with indigo naturalis for ulcerative colitis: An investigator-initiated multicenter double-blind clinical trial

1. Short-term indigo naturalis therapy demonstrated symptomatic improvement in patients with mild to moderate ulcerative colitis.

Evidence Rating Level: 1 (Excellent)

Treatment options for ulcerative colitis (UC), an inflammatory bowel disease affecting the colon and rectum, are diverse, with the addition of biologics to conventional treatment in recent years. However, patients with intolerances or unable to achieve remission with conventional treatment may consider alternatives such as natural products, which have poorly documented effects on efficacy and safety. Indigo naturalis (IN) is a blue pigment from plants such as Assam indigo, false indigo, and woad. Traditionally used as an anti-inflammatory agent in Chinese herbal medicines, they are also found in enema treatments for UC patients. In this Japanese multicentre, double-blind, randomized controlled trial, 46 patients with mild to moderate UC activity (Lichtiger index 5-10) who were intolerant of or refractory to existing treatments were randomized to receive either 5 capsules (=500mg) twice a day of either IN or placebo for 2 weeks. Only two patients from the IN group had received prior treatment with biologics and patients who received recent UC intervention or increased 5-ASA or steroid use were excluded. At baseline, the IN group had a higher mean Lichtiger index (9.04 vs 7.47). After administration, the mean Lichtiger index in the IN group had significantly improved (9.04+1.92 to 4.48+2.21, p=0.01) and was significantly lower than that of the placebo group (p=0.0019), which showed no change. In terms of adverse events, 5 patients from the IN group experienced mild headaches, which was not significantly different from placebo (vs 1 patient from the placebo group, p=0.141). As well, liver enzymes in the IN group were significantly elevated but were all within normal ranges. No severe adverse events, such as pulmonary arterial hypertension or intussusception, were reported at 24 weeks. While this study showed significant improvement on a symptomatic scale after two weeks of IN administration for UC, longer trials are needed to study its efficacy and safety, which could allow for endoscopic evaluation of disease remission.


Children with congenital heart disease exhibit seasonal variation in physical activity

1. Children with congenital heart disease experience seasonal peaks (late spring and autumn) and dips (winter and summer school holidays) in physical activity.

Evidence Rating Level: 1 (Excellent)

Occurring in 1 of 100 live births, congenital heart disease (CHD) is the most common congenital defect in newborns. WIth survival rates increasing in children with moderate to complex forms of CHD, so is the prevalence of CHD across all age ranges. Due to the increased risk of cardiovascular events that CHD confers, physical activity is an important, modifiable determinant of long-term cardiovascular health and quality of life. Consequently, the trend of declining physical activity as children with CHD age is concerning, but is difficult to assess. Understanding seasonal patterns in physical activity for this population is also important in providing appropriate recommendations. This prospective cohort study was conducted at BC Children’s Hospital in Vancouver, Canada, with 156 participants, children and adolescents aged 9-16 years old. Participants wore commercial activity trackers (Fitbit Charge 2), which collected daily step count continuously for 1 year, and also completed physical activity questionnaires (PAQ) and wore accelerometers to estimate daily mean moderate-to-vigorous physical activity (MVPA). Fitbit data illustrated clear peaks in physical activity in late spring and autumn, with a severe dip in July and August corresponding to local school holidays and a long trough during colder winter months. 23% of children overall met the daily recommended step goal (> 12 000 steps/day), with 36% in spring, 19% in summer, 30% in autumn, and 12% in winter (p<0.001). No significant differences were found between seasons in either mean PAQ score or MVPA. 26% of children achieved at least 60 minutes of MVPA daily (33%, 11%, 20%, and 39% in spring, summer, autumn, and winter). While walking and running were the most common activities throughout the year, the questionnaires found unstructured activity (ie tag) decreased during school holiday and structured activities (ie basketball, soccer) were more prevalent during the school year. These results suggest promoting season-specific activities and targets to increase activity levels, such as encouraging more family-based activity during school holiday and indoor basketball during colder months. As well, the Fitbits met with higher compliance than traditional accelerometers, while questionnaires alone may not provide valid estimates of physical activity outside the school year. Thus, commercial activity trackers may be a powerful tool in future studies to capture physical activity data continuously and understand long-term variations.


New Cancer Diagnosis After Bleeding in Anticoagulated Patients With Atrial Fibrillation

1. Gastrointestinal, genitourinary, or bronchopulmonary bleeding in anticoagulated patients with atrial fibrillation have been associated with higher rates of respective cancer diagnoses.

Evidence Rating Level: 2 (Good)

Recent registry data suggests that diagnoses of atrial fibrillation (AF) have been associated with higher incidence rates of cancer. Bleeding episodes in anticoagulated patients often unmask preexisting cancers, as oral anticoagulants (OACs) can be a “bleeding stress test”. Consequently, this retrospective cohort study explored whether these bleeding episodes should be an indicator to screen for occult cancer in AF patients on anticoagulation. A total 8 753 patients with AF from CardioCHUVI-AF (Retrospective Observational Registry of Patients with Atrial Fibrillation from Vigo’s Health Area) were analyzed, with a mean age of 82.7 years. 69.6% of patients were on Vitamin K antagonists and 30.4% on direct OACs (DOACs), and no patients had prior history of cancer; these patients were compared to non-anticoagulated patients (n= 1923). Over the 3-year follow-up, 24.8% of the anticoagulated patients experienced clinically relevant bleeding while 5.5% were diagnosed with cancer. 9.1% of patients with bleeds were subsequently diagnosed with cancer, which was 3-fold higher hazard than those without bleeding (adjusted HR 3.2, CI 2.6-3.9). Gastrointestinal, genitourinary, and bronchopulmonary bleeding were each associated with a 13-fold, 18-fold, and 15-fold higher hazard of new gastrointestinal, genitourinary, and bronchopulmonary cancer diagnoses respectively. On the other hand, bleeding in other places was associated with a lower cancer diagnosis rate (HR 2.3, 95% CI 1.5-3.6). While non-anticoagulated AF patients, of which 55.7% were prescribed antiplatelet therapy, the cumulative incidence of cancer was similar and bleeding events were also associated with an increased risk of subsequent cancer diagnosis (adjusted HR 1.8, 95% CI 1.1-29). However, a significantly higher percentage of patients were diagnosed with cancer after a bleeding episode in the anticoagulated group (41.3% vs 17.7%, p<0.0001). In terms of time of diagnosis after a bleeding event, 18.2% were diagnosed in the first month (29.5% after a major bleed), and 35.9% were diagnosed within 6 months after bleeding (61.5% after a major bleed).  While this shows greater bleeding was associated with cancer, 60.6% of cancer diagnoses followed minor bleeding. These findings demonstrate that not only can evaluating bleeding lead to early detection of occult gastrointestinal, genitourinary, and bronchopulmonary cancers and often within 6 months of the event, this association strengthens with the severity of bleeding. Further studies should analyze characteristics of the cancers diagnosed such as staging and/or explore other possible risk factors.


A Randomized Trial on the Effect of Phosphate Reduction on Vascular End Points in CKD (IMPROVE-CKD)

1. Non-calcium-based phosphate binders did not affect arterial stiffness or aortic calcification compared to placebo in moderate-to-severe chronic kidney disease.

Evidence Rating Level: 1 (Excellent)

Abnormal phosphate homeostasis is characteristic of chronic kidney disease, with hyperphosphatemia strongly associated with increased arterial stiffness secondary to calcification. Positive phosphate balance may contribute to rising fibroblast growth factor 23 (FGF23) levels. Both high FGF23 levels and arterial stiffness and calcification are associated with worsening kidney function and cardiovascular events and mortality. Although calcium-based phosphate binders are most commonly prescribed to treat hyperphosphatemia, non-calcium-based phosphate binders, like lanthanum carbonate, have been associated with reduced vascular calcification. Consequently, limited trials have described non-calcium-based phosphate binder therapy lowering serum phosphate and FGF23 levels; however, their effects on cardiovascular markers remain unknown. IMPROVE-CKD, or the IMpact of Phosphate Reduction on Vascular Endpoints in CKD, is an investigator-initiated, multicentre, international,double-blinded, placebo-controlled trial. 138 participants with stage 3b-4 CKD (eGFR 15-44mL/min/1.73m2) with normophosphatemia were randomized 1:1 to receive either 500mg lanthanum carbonate or matched placebo three times daily for 96 weeks. By the end of the trial, no significant differences were seen in the primary endpoint, mean pulse wave velocity (PWV), or in abdominal aortic calcification (AAC), serum phosphate, parathyroid hormone, FGF23 levels, or 24-hour urinary phosphate. At baseline, there was a greater proportion of AAC in the lanthanum arm (86% vs 77% in placebo, p=0.23). Serious adverse events occurred at similar rates between the groups (46% lanthanum vs 47% placebo), next to a significantly higher rate of life-threatening events in lanthanum (3% vs 0%, p=0.06). The study cohort in general was at a high cardiovascular risk at baseline, with a high mean PWV level (>10m/s) and a high prevalence of AAC (81%). Advanced arterial stiffness and calcification may have contributed to the lack of effect seen with the intermediate cardiovascular outcomes measured. Achievement of only 57% of target recruitment also led to underpowering of the study. Nevertheless, this is the largest and longest placebo-controlled study of its kind and its results cannot justify treating moderate-to-advanced CKD with phosphate binders to reduce cardiovascular risk in normophosphatemia. Further studies that are adequately powered could target a cohort with positive phosphate balance to assess whether phosphate-lowering therapies would improve patient outcomes.

Image: PD

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