2 Minute Medicine Rewind July 1, 2019

Effect of 1-Month Dual Antiplatelet Therapy Followed by Clopidogrel vs 12-Month Dual Antiplatelet Therapy on Cardiovascular and Bleeding Events in Patients Receiving PCI: The STOPDAPT-2 Randomized Clinical Trial

While dual antiplatelet therapy (DAPT) is the standard of care post-percutaneous coronary intervention (PCI) using drug-eluting stents (DES), the optimal duration of therapy remains controversial. American and European guidelines recommend DAPT for a minimum of 12 months for acute coronary syndrome (ACS), and at least 6 months in stable coronary artery disease (CAD) without high bleeding risk. Evidence has shown short-term DAPT is associated with lower bleeding risk without a significant increase in ischemic events. With the introduction of lower risk of stent thrombosis with newer DES and lower incidence of myocardial infarction with new medical therapies, minimizing bleeding risk with potentially shorter durations of therapy has been a growing consideration. The STOPDAPT (Short and Optimal Duration of Dual Antiplatelet Therapy After Everolimus-Eluting Cobalt-Chromium Stent) study found that the incidence of adverse events associated with 3-month DAPT post-DES was acceptable compared to a historical control. In the current study, the STOPDAPT-2 open-label non-inferiority trial, researchers examined the incidence of adverse events with 1 month of DAPT compared to the standard 12 months of DAPT after DES implantation. As part of this randomized clinical trial, 3045 patients across 90 Japanese hospitals were randomized between 2015 and 2017 to receive either 1 month of DAPT followed by clopidogrel monotherapy or 12-month aspirin (ASA)-clopidogrel DAPT. The primary outcome was a composite of cardiovascular mortality, myocardial infarction, ischemic or hemorrhagic strokes, definite stent thrombosis or major and minor bleeding at 12 months. A relative non-inferiority margin of 50% was used. Researchers found that one-month DAPT was found both non-inferior and superior to 12-month DAPT for the primary composite endpoint (2.36% vs. 3.70%, absolute difference -1.34%, 95% CI -2.57% to -0.11%; HR 0.64, 95% CI 0.42 to 0.98; p<0.001 for non-inferiority; p=0.04 for superiority). The secondary endpoint of cardiovascular death, myocardial infarction, ischemic or hemorrhagic stroke, or definite stent thrombosis (cardiovascular endpoint) occurred in 1.96% of patients receiving 1-month DAPT versus 2.51% in the 12-month group (HR 0.79, 95% CI 0.49 to 1.29; p=0.005 for non-inferiority; p=0.34 for superiority). Bleeding occurred in 0.41% of patients in the 1-month DAPT group compared to 1.54% of patients in the control group (HR 0.26, 95% CI 0.11 to 0.64; p=0.004 for superiority). This study therefore suggests that 1 month of DAPT followed by clopidogrel monotherapy is both non-inferior and superior to prolonged 12-month DAPT post-PCI with DES, with significantly lower rates of composite cardiovascular and bleeding events.

Physical activity trajectories and mortality: population based cohort study

While numerous studies have previously examined associations between physical activity and mortality, cardiovascular disease and certain cancers, the majority of this evidence has been cross-sectional, single-timepoint data, or has relied on a single baseline physical activity assessment for correlation. Few studies have examined physical activity trajectories over time, and subsequent risks of mortality. Of these, few have accounted for concurrent changes in other lifestyle factors. The aim of this population-based cohort study of community-based adults in the United Kingdom (n=14,599) was to examine associations of baseline and long-term physical activity trajectories with all-cause, cardiovascular and cancer-related mortalities. Study subjects were recruited from community general practices between 1993 and 1997 as part of the European Prospective Investigation into Cancer and Nutrition-Norfolk (EPIC-Norfolk). They were assessed at baseline, and were followed up until 2004 at three follow-up time-points by way of postal questionnaires and clinic visits to assess habitual physical activity and covariate lifestyle and clinical risk factors. Of note, quasi-continuous and marginalized values of physical activity energy expenditure (PAEE) in units of kilojoules (kJ)/kg/day were derived from three levels of occupational activity (unemployed or sedentary occupation, standing occupation, and physical or heavy manual occupation). Levels of leisure time physical activity were also ascertained through questionnaires. All participants were followed up using data from the Office of National Statistics until 2016 for mortality endpoints, and death certificates were used to ascertain causes of death. Primary outcome measures were all-cause, cardiovascular and cancer-related mortality. Over 171,277 person-years of follow-up, 3,148 deaths were observed, including 950 cardiovascular disease-related and 1,091 cancer-related deaths. For each 1 kJ per kilogram per day per year increase (equivalent to a trajectory of inactivity to meeting minimum physical activity guidelines as per the World Health Organization over 5 years), lower risks of all-cause mortality (HR 0.76, 95% CI 0.71 to 0.82), cardiovascular disease-related (HR 0.71, 95% CI 0.62 to 0.82) and cancer-related mortality (HR 0.89, 95% CI 0.79 to 0.99) were observed. Compared to consistently inactive individuals, increasing physical activity trajectories were associated with lower risks of all-cause mortality. Meeting and maintaining minimum physical activity guidelines (150 minutes per week of moderate-intensity activity) was associated with potentially preventing 46% of physical inactivity-related deaths. This study’s findings therefore indicate that middle-aged and older community-dwelling adults benefit significantly in terms of lifetime longevity with increased physical activity in addition to other lifestyle changes, with adherence to minimum physical activity standards having the potential to prevent close to half of inactivity-related deaths. These results encourage an increased focus on meeting physical activity standards at a population and public health level, particularly during mid and late life.

Effect of P2Y12 Inhibitor Monotherapy vs Dual Antiplatelet Therapy on Cardiovascular Events in Patients Undergoing Percutaneous Coronary Intervention: The SMART-CHOICE Randomized Clinical Trial

The current standard therapy following percutaneous coronary intervention (PCI) with drug-eluting stents (DES) is dual antiplatelet therapy (DAPT) with aspirin plus a P2Y12 inhibitor, followed by aspirin (ASA) monotherapy. P2Y12 inhibitor monotherapy has recently been suggested as an alternative to DAPT, with studies showing reduced risk of subsequent ischemic events compared to ASA in those with cardiovascular disease or undergoing PCI, and lower bleeding risk with comparable thrombotic risks compared to DAPT in those with strokes or transient ischemic attacks. The Smart Angioplasty Research Team: Comparison Between P2Y12 Antagonist Monotherapy vs. Dual Antiplatelet Therapy in Patients Undergoing Implantation of Coronary Drug-Eluting Stents (SMART-CHOICE) open-label, non-inferiority randomized trial aimed to compare P2Y12 inhibitor monotherapy to DAPT in patients receiving PCI with DES. As part of this study, 2993 patients undergoing PCI with DES from 33 Korean hospitals were randomized to receive either DAPT with ASA plus a P2Y12 inhibitor for 3 months followed by monotherapy with a P2Y12 inhibitor alone or DAPT for 12 months. The primary outcome was major adverse cardiac and cerebrovascular events (MACE) (composite of all-cause mortality, myocardial infarction and stroke) at 12 months following PCI, while secondary outcomes included individual components of the composite primary outcome and bleeding endpoints. A non-inferiority margin of 1.8% was established. With follow-up for the primary endpoint complete for 97.1% of patients receiving P2Y12 monotherapy and 97.5% of those receiving DAPT, MACE occurred in 2.9% of the former and 2.5% of the latter groups (estimated difference 0.4%, 1-sided 95% CI -∞% to 1.3%, p=0.007 for noninferiority). Bleeding occurred in 2.0% of the P2Y12 monotherapy group, and 3.4% of the DAPT group (estimated difference 0.58%, 1-sided 95% CI 0.36% to 0.92%). No significant differences were observed between groups in terms of all-cause mortality (HR 1.18, 95% CI 0.63 to 2.21, p=0.61), myocardial infarction (HR 0.66, 95% CI 0.31 to 1.40, p=0.28) and stroke (HR 2.23, 95% CI 0.78 to 6.43, p=0.14) as individual endpoints. Study findings suggest that P2Y12 monotherapy after 3 months of DAPT is non-inferior to prolonged DAPT in patients undergoing PCI intervention with regards to MACE, and is associated with a lower rate of clinically significant bleeding.

Investigating causal relations between sleep traits and risk of breast cancer in women: Mendelian randomization study

Previous studies have provided evidence for an association between circadian disruption and breast cancer risk. However, studies examining sleep traits such as chronotypes, insomnia symptoms or degree of sleep disruption with breast cancer risk have been limited or inconclusive. Genetic variants associated with chronotype, sleep duration and insomnia symptoms have been recently identified in large genome-wide association studies. The objective of this prospective cohort study was to assess whether genetic variants associated with chronotype, sleep duration and insomnia symptoms to examine whether these sleep traits have a causal effect on breast cancer risk. Female data from the United Kingdom Biobank (n=156,848) was used to perform a one-sample Mendelian randomization analysis, and estimates were compared with conventional observational multivariable regression results. A two-sample Mendelian randomization analysis was also conducted using data from the Breast Cancer Association Consortium (BCAC) (122,977 cases, 105,974 controls). Self-reported chronotype, average sleep duration, and insomnia symptom responses were gathered at baseline. Single nucleotide polymorphisms (SNP) associated with the three sleep traits as derived and validated in independent cohorts were also used in analysis. Participants were followed through record linkage via the National Health Service central registers for first diagnosis of breast cancer or breast cancer listed as the underlying cause of death to identify prevalent and incident breast cancer diagnoses. Based on multivariable regression analyses, researchers found that morning preference was inversely associated with breast cancer (HR 0.95, 95% CI 0.93 to 0.98 per category increase), whereas no significant association was found with sleep duration or insomnia symptoms. The former association was supported by two-step Mendelian randomization analysis (inverse variance weighted OR 0.88, 95% CI 0.82 to 0.93 per category increase). Two-step analysis also showed harmful effects of increased sleep duration (OR 1.19, 95% CI 1.02 to 1.39 per category increase). This study therefore shows that there may be a protective effect of morning preference with respect to breast cancer risk. Findings from this study also suggest that increased sleep duration may be associated with increased breast cancer risk.

Association of Opioid Overdose With Opioid Prescriptions to Family Members

The opioid epidemic is a growing public health emergency. To curb opioid misuse and overdoses, comprehensive prescription drug monitoring programs and laws imposing limits on daily supply or dosage of prescriptions, among other strategies, have emerged. Recent evidence suggests that most individuals who misuse opioids obtain them from family members. This nested case-control study aimed to examine whether opioid prescriptions to family members is associated with increased likelihood of overdose in individuals with no previous prescription opioid use. Using data from a de-identified administrative database and medical claims for Americans covered by a large national commercial insurance company between 2004 and 2015, individuals with a minimum of 12 months of continuous database enrollment, and at least 1 family member in the database, were studied. Incident opioid overdose cases, identified through a first emergency department visit or hospitalization for such, without prior history of opioid overdose or dispensing, and four control individuals being followed with each of the cases’ overdose dates, were identified. Occasions in which opioid prescriptions were dispensed to family members during follow-up (between 12-month baseline period and overdose date) were assessed across cases and controls, and the total and per-day morphine milligram equivalent (MME) for all opioids dispensed to family members was calculated. The primary outcome was the individual likelihood of opioid overdose resulting in hospitalization or emergency department visit among individuals whose family members had been dispensed opioids compared to controls without such an exposure. Overall, 2,303 individuals experienced an opioid overdose. Researchers found that prior family history of opioid prescriptions was significantly associated with individual overdose (OR 2.89, 95% CI 2.59 to 3.23), and increasing amount of opioid prescription was associated with increased likelihood of overdose.  The findings of this study therefore demonstrate an association between family member exposure to prescription opioids and individual overdose risk, despite no prior direct exposure. This association was found to be persistent in children and adolescents. These results emphasize the importance of increased protective interventions around dispensing limits, proper disposal of prescription medications, educational efforts, secure medication delivery mechanisms and other strategies to reduce risk of opioid overdose among family members of prescription users.

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