2 Minute Medicine Rewind June 15, 2020

Risk of Hospitalization with Hemorrhage Among Older Adults Taking Clarithromycin vs Azithromycin and Direct Oral Anticoagulants

1. Co-prescription of clarithromycin and direct oral anticoagulants was associated with a higher rate of 30-day hospitalization with hemorrhage when compared with co-prescription of azithromycin.

Evidence Rating Level: 2 (Good)

In recent years, direct oral anticoagulants (DOACs) like apixaban and rivaroxaban have overtaken vitamin K antagonists as the anti-coagulation drugs of choice. DOACs are known to be substrates of CYP3A4 enzyme complexes, and are thus susceptible to potentially dangerous drug-drug interactions. This retrospective cohort study involved 24,943 older adults (M [SD] age = 77.6 [7.2] years, 51.0% women) living in Ontario, Canada, taking DOACs, and assessed whether co-prescription of either clarithromycin or azithromycin, macrolide antibiotics commonly prescribed for respiratory infections and known to affect CYP3A4 complexes, were associated with an increased risk of hemorrhage requiring hospitalization. The primary outcome was hospitalization for major hemorrhage, defined as upper or lower gastrointestinal bleeds and intracerebral, subarachnoid, or other nontraumatic intracranial bleeds, within 30 days of either clarithromycin or azithromycin prescription. The most commonly prescribed DOACs among participants were rivaroxaban (n = 9,972 [40.0%]), followed by apixaban (n = 7,953 [31.9%]), and, lastly, dabigatran (n = 7,018 [28.1%]). The study found that major hemorrhage within 30 days occurred in 51 of 6,592 (0.77%) patients taking clarithromycin and 79 of 18,351 (0.43%) patients taking azithromycin (HR 1.81, 95% CI 1.27 to 2.57, absolute risk difference 0.34%). Adjustment for proton pump inhibitor use as well as DOAC type and dosage showed that the higher rate of hemorrhage in patients taking clarithromycin was consistent (aHR 1.71, 95% CI, 1.20 to 2.45). Among secondary analyses conducted, a broadening of the definition of hemorrhage to include any bleeding episode or receipt of a blood transfusion also showed a higher rate of bleeds (aHR 1.53, 95% CI 1.21 to 1.94) in patients taking clarithromycin (n = 109 [1.65%]) compared with patients taking azithromycin (n = 199 [1.08%]). Taken together, these findings suggest that among older adults, the co-prescription of clarithromycin and DOACs is associated with an increased risk of 30-day hospitalization for hemorrhage when compared with azithromycin. Providers should be aware of this potential risk when prescribing macrolide antibiotics to patients on DOACs.


Interventions supporting long term adherence and decreasing cardiovascular events after myocardial infarction (ISLAND): pragmatic randomised controlled trial

1. Mailers and telephone reminders together significantly increased the likelihood of completing cardiac rehabilitation at 12 months among individuals who have experienced a myocardial infarction.

Evidence Rating Level: 2 (Good)

Secondary prevention following a myocardial infarction (MI) is important to reduce subsequent morbidity and mortality. Though recommended drug regimens and cardiac rehabilitation have been shown to be effective forms of secondary prevention, non-adherence is notoriously common, and around half of patients discontinue therapy by 12 months following their MI. This pragmatic, three-arm, single-blinded randomized controlled trial involved 2,632 participants from 9 cardiac centers in Ontario, Canada, randomized 1:1:1. 878 participants (M [SD] age = 66.8 [12.6] years, 71.3% male) receiving mail-out reminders and 878 participants (M [SD] age = 65.9 [12.1] years, 71.3% male) receiving mail-out reminders plus telephone calls were compared with 876 participants (M [SD] age = 66.8 [12.5] years, 71.2% male) receiving usual care for adherence to recommended pharmacotherapy as well as attendance at and completion of cardiac rehabilitation. Primary outcomes were adherence to recommended drugs as measured on an ordinal scale and completion of cardiac rehabilitation, both assessed at 12 months post-MI. No significant difference in medication adherence was observed among participants in either intervention arm compared with usual care. However, patients receiving mail-out reminders plus telephone calls had significantly greater odds of fully completing cardiac rehabilitation when compared with those receiving usual care (OR 1.55, 95% CI 1.18 to 2.03, p = 0.007). These findings were consistent on the absolute scale (adjusted risk difference 9.4%, 95% CI 3.5% to 15.4%). Patients who received only mail-out reminders had a higher, but statistically insignificant, rate of cardiac rehabilitation completion (OR 1.19, 95% CI 0.95 to 1.50, p = 0.34), with findings again being consistent on the absolute scale (adjusted risk difference 3.7%, 95% CI -1.0% to 8.4%). Overall, this trial showed that an educational intervention delivered by mail and telephone to post-MI patients can be a cost-effective route to significantly increase adherence to cardiac rehabilitation but not to medication.


Cigarette Smoking and Incident Stroke in Blacks of the Jackson Heart Study

1. Current smoking was found to be associated with an increased risk of stroke among blacks in a dose-dependent relationship.

2. Former smokers did not appear to be at an increased risk of stroke when compared with non-smokers, suggesting a reduction in stroke incidence associated with smoking cessation.

Evidence Rating Level: 2 (Good)

Stroke is a leading cause of morbidity and mortality in the United States, and smoking is known to be an independent, modifiable risk factor for development of stroke. Blacks are substantially more likely to develop, and die from, a stroke when compared with other racial groups. To address the limited data regarding cigarette smoking and incident stoke in blacks, this prospective cohort study utilized participants of the Jackson Heart Study, the largest, single-site prospective cohort study designed to examine risk factors for heart disease in blacks. A total of 4,410 participants were included, representing 83.1% of the original cohort. In addition to stroke incidence, the investigators measured carotid intimal medial thickness (CIMT), a marker of atherosclerosis that has been correlated with the incidence of stroke. A total of 3,083 participants (M [SD] age = 53.1 [13.0] years, 30% male) identified as never having smoked, 781 (M [SD] age = 59.2 [11.2] years, 47% male) as former smokers, and 546 (M [SD] age = 51.6 [11.1] years, 51% male) as current smokers. During follow-up, 183 participants developed stoke. Compared with non-smokers, current smokers were found to be at an increased risk of stroke (HR 2.57, 95% CI 1.75 to 3.79), whereas the risk of stroke was not different among former smokers (HR 1.16, 95% CI 0.81 to 1.68). A dose-dependent risk of stroke was seen in current smokers who reported using between 1 and 19 cigarettes daily (HR 2.28, 95% CI 1.38 to 3.86) and those who reported using greater than 20 cigarettes daily (HR 2.78, 95% CI 1.47 to 5.28). CIMT was increased in both current and former smokers when compared with non-smokers after adjusting for age and sex. Similar to the previous findings, a significant, dose-dependent increase in CIMT was seen in participants smoking 1 to 19 cigarettes daily (β coefficient 0.05, 95% CI 0.0 to 0.1, p = 0.02) and in participants smoking greater than 20 cigarettes daily (β coefficient 0.08, 95% CI 0.02 to 0.14, p = 0.008) when compared with non-smokers. This study highlights the increased risk of stoke associated with smoking among blacks and emphasizes the need for targeted public health interventions to modify this risk. It also suggests that smoking cessation has a role in reducing incident stroke among blacks.


Psychosocial, behavioral and clinical correlates of children with overweight and obesity

1. When compared with overweight and non-severe obesity among adolescents, severe obesity was associated with higher rates of eating when bored, decreased participation in sports and activities, and higher levels of stress.

2. Median hs-CRP, as well as prevalence of asthma, depression, and obstructive sleep apnea were elevated among adolescents with severe obesity.

Evidence Rating Level: 2 (Good)

Rates of obesity (≥95th percentile of a sex-specific BMI) and severe obesity (≥120% of 95th percentile of a sex-specific BMI) among children are steadily increasing in the United States. Severe obesity, in particular, increased from 4.0% between 1999 and 2000 to 6.0% between 2015 and 2016, with the highest prevalence (7.7%) seen among adolescents ages 12 to 19 years. Children and adolescents with severe obesity are at an increased risk for abnormal cardiovascular risk factors, asthma, depression, anxiety, and poor psychosocial wellbeing. This cross-sectional cohort study involving 105 children aimed to identify the factors vis-à-vis psychosocial, behavioral, and clinical metrics separating adolescents with severe obesity (n = 54, M age = 17.06 years, 40.7% male) from those with non-severe obesity (n = 31, M age = 14.40 years, 38.7% male) and overweight (n = 20, M age = 14.40 years, 35.0% male). Across the weight categories, median total body fat was shown to significantly increase and correlate strongly with BMI (r = 0.76, p ≤0.001). Among participants ≥13 years with obesity, eating when bored was more frequently reported compared with participants with overweight (p = 0.022). Participants with severe obesity were more likely to report not engaging in sports or other organized activities (p = 0.044). The study revealed no correlation between BMI and total cholesterol (r = -0.054, p = 0.588), LDL-C (r = 0.078, p = 0.432), or triglyceride levels (r = 0.161, p = 0.102). However, comparison with HDL revealed an inverse relationship (r = -0.352, p <0.001). Additionally, a strong difference between groups was observed for hs-CRP levels, with median hs-CRP among those with severe obesity 3 to 4 times high than those with overweight or non-severe obesity (p <0.001); this exceeded the cutoff (3.4 mg/L) for an elevated risk of cardiovascular disease. Severe obesity was associated with significantly higher levels of asthma (p = 0.007), depression (p = 0.02), and obstructive sleep apnea (p = 0.04). Finally, subjects with severe obesity reported higher median stress levels (p = 0.035). This study re-emphasizes the importance of weight control as an important lifestyle factor, and highlights some of the health behaviors and risks associated with severe obesity among adolescents which may provide avenues for future health promoting interventions.


Association of Symptoms of Depression With Cardiovascular Disease and Mortality in Low-, Middle-, and High-Income Countries

1. Depressive symptoms were associated with increased incident cardiovascular disease and all-cause mortality across multiple countries and communities at varying stages of economic development.

2. The strength of the association was highest in populations living in urban areas.

Evidence Rating Level: 2 (Good)

Depression has been shown to be associated with increased risks of cardiovascular disease (CVD), cancers, and mortality. As these studies have nearly exclusively been carried out in high-income countries however, it is not clear if those findings are transferrable to resource-poor populations. This multicenter, population-based cohort study involved 145,862 participants from 370 urban and 341 rural communities across 5 low-, 5 lower-middle-, 7 upper-middle-, and 4 high-income countries. Individuals with 4 or more self-reported depressive symptoms (n = 15,983, M [SD] age = 49.2 [9.3] years) were compared with those reporting less than 4 (n = 129,879, M [SD] age = 50.2 [9.7] years) for incident CVD, all-cause mortality, and a combined measure of either incident CVD or all-cause mortality. Incidence of CVD (HR 1.17, 95% CI 1.08 to 1.27, p <0.001), mortality (HR 1.18, 95% CI 1.11 to 1.26, p <0.001), and combined CVD and all-cause mortality (HR 1.20, 95% CI 1.13 to 1.27, p<0.001) were shown to be significantly increased among participants reporting 4 or more depressive symptoms, increasing overall risk of incident CVD and all-cause mortality by 14% and 17%, respectively. Relative risk for all primary outcomes was shown to significantly (p <0.001) trend upward with more self-reported depressive symptoms, from HR 1.05 (95% CI, -0.92 to 1.19) among those reporting 1 symptom to HR 1.24 (95% CI 1.12 to 1.37) among those reporting 7 symptoms. HRs for depression were similar in the different geographical regions studied (p = 0.56) and in both income cohorts (p = 0.52); however, the risk doubled in urban communities (HR 1.23, 95% CI 1.13 to 1.34) compared with rural communities (HR 1.10, 95% CI 1.02 to 1.19, p = 0.001). Finally, among men (HR 1.27, 95% CI 1.17 to 1.38) the association between depressive symptoms and all primary outcomes compared with women (HR 1.14, 95% CI 1.06 to 1.23) was significantly stronger (p <0.001). Overall, this study demonstrates the association between depressive symptoms and CVD and mortality that exist in countries across various stages of development and geographical context. Given that strength of the association was highest in urban areas, government and healthcare policy must be directed to address this relationship as the majority of the global population is projected to live in urban areas by the mid-century.

Image: PD

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