Clinical factors associated with day-to-day peak pain severity in individuals with chronic migraine: A cohort study using daily prospective diary data.

OBJECTIVE: To describe the association between day-to-day peak pain severity and clinical factors in individuals with chronic migraine (CM). BACKGROUND: Little is known about how clinical factors relate to day-to-day pain severity in individuals with CM. METHODS: Adults with CM were enrolled into this observational prospective cohort study that collected daily data about headache, associated symptoms, and lifestyle factors using a digital health platform (N1-Headache™) for 90 days. "Migraine days" were defined as days in which a headache occurred that had features described by the International Classification of Headache Disorders criteria. On these days, peak pain severity was recorded on a 4-point scale; on non-headache days peak pain severity was imputed as "0/none". The associations between peak pain severity and 12 clinical factors were modeled and adjusted for sex, age, daily headache, presence of menstrual bleeding, day of the week, and disability. All numerical and Likert scale variables were standardized prior to analysis. RESULTS: Data were available for 392 participants (35,280 tracked days). The sample was predominantly female (90.6%), with a mean (standard deviation) age of 39.9 (12.8) years. In the final multivariable model with random intercept and slopes, higher than typical self-reported levels of standardized stress (odds ratio [OR] 1.07, 95% confidence interval [CI] 1.04-1.11), standardized irritability (OR 1.05, 95% CI 1.02-1.08), standardized sadness (OR 1.05, 95% CI 1.02-1.07), fatigue (OR 1.25, 95% CI 1.15-1.36), eyestrain (OR 1.38, 95% CI 1.26-1.52), neck pain (OR 1.94, 95% CI 1.76-2.13), skin sensitivity (OR 1.61, 95% CI 1.44-1.80), and dehydration (OR 1.29, 95% CI 1.18-1.42) were associated with higher reported peak pain severity levels, while standardized sleep quality (OR 0.96, 95% CI 0.93-0.99) and standardized waking feeling refreshed (OR 0.84, 95% CI 0.81-0.88) were associated with lower reported peak pain severity levels. The inclusion of a random intercept and random slopes improved upon more parsimonious models and illustrated large differences in individuals' reporting of peak severity according to the levels of the associated clinical factors. CONCLUSION: Our data showed that the experience of CM, from a pain severity perspective, is complex, related to multiple clinical variables, and highly individualized. These results suggest that future work should aim to study a personalized approach to both medical and behavioral interventions for CM based on which clinical factors relate to the individual's experience of pain severity.

The role of avoiding known triggers, embracing protectors, and adhering to healthy lifestyle recommendations in migraine prophylaxis: Insights from a prospective cohort of 1125 people with episodic migraine.

OBJECTIVES/BACKGROUND: Until recently, guidelines for migraine prevention recommended avoiding known migraine headache triggers. Adhering to healthy lifestyle behaviors is also recommended. In a recent cohort study many triggers were found to decrease the probability of migraine attacks in some individuals. The extent to which people with migraine adhere to healthy lifestyle recommendations is unknown. We set out to determine if known migraine trigger factors and daily adherence to healthy lifestyle recommendations are associated with decreased probability of migraine attacks in some individuals. METHODS: This was an observational longitudinal cohort study of individuals with episodic migraine who registered to track their headache symptoms and daily exposure to trigger factors prospectively using a migraine-headache electronic diary during 90 days. We assessed whether triggers increased or decreased migraine attack risk in each individual. In addition, we calculated the proportion of days in which the individual adhered to lifestyle recommendations. RESULTS: We analyzed a total of 1125 individuals contributing 14,080 migraine attacks. Out of 47 triggers, 24 were more often associated with decreased rather than with increased migraine attack risk. Most pronouncedly this was true for caffeine, alcohol, and chocolate; happiness; relaxedness; sleep factors (longer duration, higher quality, and waking up refreshed); and physical activity. People who were more compliant with healthy behaviors, especially keeping good hydration and regular meals, were significantly older and had been diagnosed with migraine disease for a longer period, compared to those who were less compliant. Overall, exercising ≥3 times a week was the least followed recommendation. CONCLUSION: Many triggers behaved as protectors in a non-negligible proportion of individuals with episodic migraine, challenging the recommendation of avoiding known triggers. Low adherence to healthy lifestyle recommendations demonstrates an opportunity to increase awareness among people with migraine.

Alcohol as a trigger of migraine attacks in people with migraine. Results from a large prospective cohort study in English-speaking countries.

OBJECTIVE: To assess whether alcohol intake is associated with the onset of migraine attacks up to 2 days after consumption in individuals with episodic migraine (EM). BACKGROUND: Although alcohol has long been suspected to be a common migraine trigger, studies have been inconclusive in proving this association. METHODS: This was an observational prospective cohort study among individuals with migraine who registered to use a digital health platform for headache. Eligible individuals were aged ≥18 years with EM who consumed alcohol and had tracked their headache symptoms and alcohol intake for ≥90 days. People who did not drink any alcohol were excluded. The association of alcohol intake ("Yes/No") and of the number of alcoholic beverages in the 2 days preceding a migraine attack was assessed accounting for the presence of migraine on day-2 and its interaction with alcohol intake on day-2, and further adjusted for sex, age, and average weekly alcohol intake. RESULTS: Data on 487 individuals reporting 5913 migraine attacks and a total of 40,165 diary days were included in the analysis. Presence of migraine on day-2 and its interaction with alcohol intake on day-2 were not significant and removed from the model. At the population level, alcohol intake on day-2 was associated with a lower probability of migraine attack (OR [95% CI] = 0.75 [0.68, 0.82]; event rate 1006/4679, 21.5%), while the effect of alcohol intake on day-1 was not significant (OR [95% CI] = 1.01 [0.91, 1.11]; event rate 1163/4679, 24.9%) after adjusting for sex, age, and average weekly alcohol intake. Similar results were obtained with the number of beverages as exposure. CONCLUSIONS: In this English-speaking cohort of individuals with EM who identified themselves as mostly low-dose alcohol consumers, there was no significant effect on the probability of a migraine attack in the 24 h following consumption, and a slightly lower likelihood of a migraine attack from 24 to 48 h following use.

An observational study of self-reported migraine triggers and prospective evaluation of the relationships with occurrence of attacks enabled by a smartphone application (App).

OBJECTIVE: To investigate the relationship between self-reported triggers and the occurrence of migraine attacks using a smartphone application. BACKGROUND: One of several issues around the study of migraine attack triggers is that limited available evidence supports whether self-reported triggers can induce a headache on a particular subject. METHODS: This is an observational longitudinal cohort study of individuals with migraine registered to track their headaches prospectively using a smartphone application. For 90 days, participants entered daily data about triggers (potential triggers and premonitory symptoms) that may be associated with attack risk, as well as migraine symptoms. The statistical significance of univariate associations between each trigger and migraine recurrent events was determined for each individual. Statistically identified triggers were then compared to self-reported triggers. RESULTS: In 328 individuals (290/328 [88.4%] female; mean [standard deviation] 4.2 [1.5] migraine attacks/month) the mean (standard deviation) number of triggers moderately or highly endorsed per individual was 28.0 (7.7) in individuals presented with up to 38 possible triggers. Of these, an average (standard deviation) of 2.2 (2.1) triggers per individual were statistically associated with increased risk of attacks. Even the most commonly endorsed triggers (sleep quality, stress, tiredness/fatigue, sleep duration, dehydration, neck pain, missed meals, eyestrain, mean barometric pressure, and anxiety) were statistically associated in fewer than one third of individuals suspecting each, with the exception of neck pain (117/302 [38.7%]). CONCLUSIONS: Individuals with episodic migraine believe that many triggers contribute to their attacks; however, few of these withstand statistical testing at the individual level. Improved personal knowledge of potential triggers and premonitory symptoms may help individuals adopt behavioral changes to mitigate attack risk.

Perceived stress and pain severity in individuals with chronic migraine: A longitudinal cohort study using daily prospective diary data.

OBJECTIVE: We aimed to describe patterns of peak attack severity from day-to-day, and in relation to same-day perceived stress, in individuals with chronic migraine (CM). BACKGROUND: Although changes in perceived stress are often believed to trigger attacks, little is known about the relationship between perceived stress and attack severity, and about the role of perceived stress in the day-to-day experience of individuals with CM, as opposed to those with less frequent attacks. METHODS: This was an observational prospective longitudinal cohort study among adults with CM. Daily data about headache, symptoms, and lifestyle factors were collected using the N1-Headache™ digital health platform for 90 days. Days were classified as "migraine days" when a headache occurred that met the International Classification of Headache Disorders criteria. Perceived stress was measured using a 0-10 rating scale. On migraine days, peak pain severity was recorded on a four-point categorical pain scale. Participant-level plots of daily peak severity, colored by perceived stress score, were generated. The relationship between peak severity and perceived stress was also modeled and adjusted for sex, age, continuous headache, presence of menstrual bleeding, day of the week, and disability. RESULTS: Data on 136 participants with 8216 migraine days were analyzed. Sixty-nine percent (94/136) of participants reported the same peak severity on the majority (≥50%) of their migraine days. For every one unit increase in perceived stress, the odds of reporting a higher peak severity were 10% higher (adjusted OR [95% CI] = 1.10 [1.07-1.14]). The inclusion of random effects for the intercept and slope improved the model and demonstrated that there were large differences in individuals' reporting of peak severity and in the relationship between perceived stress and peak severity. CONCLUSION: Individuals with CM report distinct patterns of peak severity from day-to-day. Although overall higher perceived stress was associated with higher peak severity, there is a substantial amount of variation between individuals in this relationship.

Between and within-woman differences in the association between menstruation and migraine days.

OBJECTIVE: To investigate between and within-woman differences in the association between menstruation and migraine days. BACKGROUND: Prior diary studies have shown that at the population level, aggregating across individuals, the odds of migraine increase during the perimenstrual window (from day -2 to day +3, where +1 is the first day of bleeding). These studies have been neither long nor large enough to assess the association between migraine and menses from an individual perspective. Consequently, existing research on menstrual-related migraine has largely overlooked between and within-woman variation that is critical for progressing clinical understanding and practice. METHODS: Intensive longitudinal data for the current study were collected in a digital platform (N1-Headache® ) that tracks individual migraine-related factors daily. Participants for the current study were actively menstruating adult (18+ years old) women who used the platform. Two variables were of primary interest, migraine day (no/yes) and menstrual status (inside or outside the 5-day perimenstrual window). RESULTS: The sample consisted of 203 women with a mean age of 35.6 (SD = 8.7) years. At baseline, the women reported an average of 30.6 (SD = 23.6) headache days over the last 3 months. Analyses were based on a total of 53,302 days (median of 150 per person), 18,520 of which were migraine days (median of 44 per person), and a total of 2,126 menstrual cycles (median of 7 per person). Results showed that the 5-day perimenstrual window was associated with a 34% increase in odds of a migraine day compared to other days (OR = 1.34, 95% CI: 1.23-1.45, p < 0.0001). Importantly, there was between and within-woman variability in the association between menses and migraine days (between-woman variability: p = 0.002; within-woman [between-cycles] variability: p < 0.0001). Exploration of these individual differences demonstrated that relationship between menses and migraine days varied more within-person across cycles than between women. DISCUSSION: This study supports previous research and demonstrates that the odds of migraine days are elevated from day -2 to day +3 of the menstrual cycle. We also show that the effect of menses on migraine days varies more within-woman than between-women. This work provides an initial foundation for better understanding menstrual-related migraine from the perspective of the individual patient.

Patterns of Perceived Stress Throughout the Migraine Cycle: A Longitudinal Cohort Study Using Daily Prospective Diary Data.

OBJECTIVES: To describe patterns of perceived stress across stages of the migraine cycle, within and between individuals and migraine episodes as defined for this study. METHODS: Individuals with migraine aged ≥18 years, who were registered to use the digital health platform N1-HeadacheTM , and completed 90 days of daily data entry regarding migraine, headache symptoms, and lifestyle factors were eligible for inclusion. Perceived stress was rated once a day at the participant's chosen time with a single question, "How stressed have you felt today?" with response options graded on a 0-10 scale. Days were categorized into phases of the migraine cycle: Ppre  = pre-migraine headache (the 2 days prior to the first day with migraine headache), P0  = migraine headache days, Ppost  = post-migraine headache (the 2 days following the last migraine day with migraine headache), and Pi  = interictal days (all other days). Episodes, defined as discrete occurrences of migraine with days in all 4 phases, were eligible if there was at least 1 reported daily perceived stress value in each phase. Individuals with ≥5 valid episodes, and ≥75% compliance (tracking 90 days in 120 calendar days or less) were eligible for inclusion in the analysis. RESULTS: Data from 351 participants and 2115 episodes were included in this analysis. Eighty-six percent of the sample (302/351) were female. The mean number of migraine days per month was 6.1 (range 2-13, standard deviation = 2.3) and the mean number of episodes was 6.0 (range 5-10, standard deviation = 1.0) over the 90-day period. Only 8 (8/351, 2.3%) participants had chronic migraine (defined as 15 or more headache days per month with at least 8 days meeting criteria for migraine). Cluster analysis revealed 3 common patterns of perceived stress variation across the migraine cycle. For cluster 1, the "let down" pattern, perceived stress in the interictal phase (Pi ) falls in the pre-headache phase (Ppre ) and then decreases more in the migraine phase (P0 ) relative to Pi . For cluster 2, the "flat" pattern, perceived stress is relatively unchanging throughout the migraine cycle. For cluster 3, the "stress as a trigger/symptom" pattern, perceived stress in Ppre increases relative to Pi , and increases further in P0 relative to Pi . Episodes were distributed across clusters as follows: cluster 1: 354/2115, 16.7%; cluster 2: 1253/2115, 59.2%, and cluster 3: 508/2115, 24.0%. Twelve participants (12/351, 3.4%) had more than 50% of their episodes fall into cluster 1, 216 participants (216/351, 61.5%) had more than 50% of their episodes fall into cluster 2, and 25 participants (25/351, 7.1%) had more than 50% of their episodes fall into cluster 3. There were 40 participants with ≥90% of their episodes in cluster 2, with no participants having ≥90% of their episodes in cluster 1 or 3. CONCLUSIONS: On an aggregate level, perceived stress peaks during the pain phase of the migraine cycle. However, on an individual and episode basis, there are 3 dominant patterns of perceived stress variation across the migraine cycle. Elucidating how patterns of perceived stress vary across the migraine cycle may contribute insights into disease biology, triggers and protective factors, and provide a framework for targeting individualized treatment plans.

Modeling and visualizing two-way contingency tables using compositional data analysis: A case-study on individual self-prediction of migraine days.

Two-way contingency tables arise in many fields, such as in medical studies, where the relation between two discrete random variables or responses is to be assessed. We propose to analyze and visualize a sample of 2 × 2 tables in the context of single-subject repeated measurements design by means of compositional data (CoDa) methods. First, we propose to visualize the tables in a quaternary diagram. Second, we show how to represent these tables by means of logratios indicating the relationship between the two variables as well as their strength and direction of dependency. Finally, we describe a technique to model those tables with a simplicial regression model. Data from a real-world study of self-prediction of migraine attack onset is used to illustrate this methodology. For each individual, the 2 × 2 table of their migraine expectation vs next day migraine occurrence is computed, generating a sample of tables. Then we visualize and interpret the prediction ability of individuals both in the simplex and in terms of logratios of components. Finally, we model the self-prediction ability with respect to demographic variables, days tracked and disease characteristics. Our application demonstrates that CoDa can be a useful tool for visualizing, modeling, and interpreting the components of 2 × 2 tables.

Rivaroxaban for Prevention of Covert Brain Infarcts and Cognitive Decline: The COMPASS MRI Substudy.

BACKGROUND AND PURPOSE: Covert brain infarcts are associated with cognitive decline. It is not known whether therapies that prevent symptomatic stroke prevent covert infarcts. COMPASS compared rivaroxaban with and without aspirin with aspirin for the prevention of stroke, myocardial infarction, and vascular death in participants with stable vascular disease and was terminated early because of benefits of rivaroxaban 2.5 mg twice daily plus aspirin over aspirin. We obtained serial magnetic resonance imagings and cognitive tests in a consenting subgroup of COMPASS patients to examine treatment effects on infarcts, cerebral microbleeds, and white matter hyperintensities. METHODS: Baseline and follow-up magnetic resonance imagings were completed in 1445 participants with a mean (SD) interval of 2.0 (0.7) years. Whole-brain T1, T2 fluid-attenuated inversion recovery, T2* sequences were centrally interpreted by blinded, trained readers. Participants had serial measurements of cognition and function. The primary end point was the proportion of participants with incident covert infarcts. Secondary end points were the composite of clinical stroke and covert brain infarcts, cerebral microbleeds, and white matter hyperintensities. RESULTS: At baseline, 493 (34.1%) participants had infarcts. Incident covert infarcts occurred in 55 (3.8%) participants. In the overall trial rivaroxaban plus aspirin reduced ischemic stroke by 49% (0.7% versus 1.4%; hazard ratio [95% CI], 0.51 [0.38-0.68]). In the magnetic resonance imaging substudy the effects of rivaroxaban+aspirin versus aspirin were: covert infarcts: 2.7% versus 3.5% (odds ratio [95% CI], 0.77 [0.37-1.60]); Covert infarcts or ischemic stroke: 2.9% versus 5.3% (odds ratio [95% CI], 0.53 [0.27-1.03]). Incident microbleeds occurred in 6.6% of participants and 65.7% of participants had an increase in white matter hyperintensities volume with no effect of treatment for either end point. There was no effect on cognitive tests. CONCLUSIONS: Covert infarcts were not significantly reduced by treatment with rivaroxaban and aspirin but estimates for the combination of ischemic stroke and covert infarcts were consistent with the effect on ischemic stroke in the overall trial. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01776424.

Rationale, design, and baseline participant characteristics in the MRI and cognitive substudy of the cardiovascular outcomes for people using anticoagulation strategies trial.

BACKGROUND: Covert vascular disease of the brain manifests as infarcts, white matter hyperintensities, and microbleeds on MRI. Their cumulative effect is often a decline in cognition, motor impairment, and psychiatric disorders. Preventive therapies for covert brain ischemia have not been established but represent a huge unmet clinical need. AIMS: The MRI substudy examines the effects of the antithrombotic regimens in COMPASS on incident covert brain infarcts (the primary outcome), white matter hyperintensities, and cognitive and functional status in a sample of consenting COMPASS participants without contraindications to MRI. METHODS: COMPASS is a randomized superiority trial testing rivaroxaban 2.5 mg bid plus acetylsalicylic acid 100 mg and rivaroxaban 5 mg bid against acetylsalicylic acid 100 mg per day for the combined endpoint of MI, stroke, and cardiovascular death in individuals with stable coronary artery disease or peripheral artery disease. T1-weighted, T2-weighted, T2*-weighted, and FLAIR images were obtained close to randomization and near the termination of assigned antithrombotic therapy; biomarker and genetic samples at randomization and one month, and cognitive and functional assessment at randomization, after two years and at the end of study. RESULTS: Between March 2013 and May 2016, 1905 participants were recruited from 86 centers in 16 countries. Of these participants, 1760 underwent baseline MRI scans that were deemed technically adequate for interpretation. The mean age at entry of participants with interpretable MRI was 71 years and 23.5% were women. Coronary artery disease was present in 90.4% and 28.1% had peripheral artery disease. Brain infarcts were present in 34.8%, 29.3% had cerebral microbleeds, and 93.0% had white matter hyperintensities. The median Montreal Cognitive Assessment score was 26 (interquartile range 23-28). CONCLUSIONS: The COMPASS MRI substudy will examine the effect of the antithrombotic interventions on MRI-determined covert brain infarcts and cognition. Demonstration of a therapeutic effect of the antithrombotic regimens on brain infarcts would have implications for prevention of cognitive decline and provide insight into the pathogenesis of vascular cognitive decline.

The effect of physical activity on mortality and cardiovascular disease in 130 000 people from 17 high-income, middle-income, and low-income countries: the PURE study.

BACKGROUND: Physical activity has a protective effect against cardiovascular disease (CVD) in high-income countries, where physical activity is mainly recreational, but it is not known if this is also observed in lower-income countries, where physical activity is mainly non-recreational. We examined whether different amounts and types of physical activity are associated with lower mortality and CVD in countries at different economic levels. METHODS: In this prospective cohort study, we recruited participants from 17 countries (Canada, Sweden, United Arab Emirates, Argentina, Brazil, Chile, Poland, Turkey, Malaysia, South Africa, China, Colombia, Iran, Bangladesh, India, Pakistan, and Zimbabwe). Within each country, urban and rural areas in and around selected cities and towns were identified to reflect the geographical diversity. Within these communities, we invited individuals aged between 35 and 70 years who intended to live at their current address for at least another 4 years. Total physical activity was assessed using the International Physical Activity Questionnaire (IPQA). Participants with pre-existing CVD were excluded from the analyses. Mortality and CVD were recorded during a mean of 6·9 years of follow-up. Primary clinical outcomes during follow-up were mortality plus major CVD (CVD mortality, incident myocardial infarction, stroke, or heart failure), either as a composite or separately. The effects of physical activity on mortality and CVD were adjusted for sociodemographic factors and other risk factors taking into account household, community, and country clustering. FINDINGS: Between Jan 1, 2003, and Dec 31, 2010, 168 916 participants were enrolled, of whom 141 945 completed the IPAQ. Analyses were limited to the 130 843 participants without pre-existing CVD. Compared with low physical activity (<600 metabolic equivalents [MET] × minutes per week or <150 minutes per week of moderate intensity physical activity), moderate (600-3000 MET × minutes or 150-750 minutes per week) and high physical activity (>3000 MET × minutes or >750 minutes per week) were associated with graded reduction in mortality (hazard ratio 0·80, 95% CI 0·74-0·87 and 0·65, 0·60-0·71; p<0·0001 for trend), and major CVD (0·86, 0·78-0·93; p<0·001 for trend). Higher physical activity was associated with lower risk of CVD and mortality in high-income, middle-income, and low-income countries. The adjusted population attributable fraction for not meeting the physical activity guidelines was 8·0% for mortality and 4·6% for major CVD, and for not meeting high physical activity was 13·0% for mortality and 9·5% for major CVD. Both recreational and non-recreational physical activity were associated with benefits. INTERPRETATION: Higher recreational and non-recreational physical activity was associated with a lower risk of mortality and CVD events in individuals from low-income, middle-income, and high-income countries. Increasing physical activity is a simple, widely applicable, low cost global strategy that could reduce deaths and CVD in middle age. FUNDING: Population Health Research Institute, the Canadian Institutes of Health Research, Heart and Stroke Foundation of Ontario, Ontario SPOR Support Unit, Ontario Ministry of Health and Long-Term Care, AstraZeneca, Sanofi-Aventis, Boehringer Ingelheim, Servier, GSK, Novartis, King Pharma, and national and local organisations in participating countries that are listed at the end of the Article.

The effect of physical activity on mortality and cardiovascular disease in 130 000 people from 17 high-income, middle-income, and low-income countries: the PURE study

Background Physical activity has a protective effect against cardiovascular disease (CVD) in high-income countries, where physical activity is mainly recreational, but it is not known if this is also observed in lower-income countries, where physical activity is mainly non-recreational. We examined whether different amounts and types of physical activity are associated with lower mortality and CVD in countries at different economic levels. Methods In this prospective cohort study, we recruited participants from 17 countries (Canada, Sweden, United Arab Emirates, Argentina, Brazil, Chile, Poland, Turkey, Malaysia, South Africa, China, Colombia, Iran, Bangladesh, India, Pakistan, and Zimbabwe). Within each country, urban and rural areas in and around selected cities and towns were identified to reflect the geographical diversity. Within these communities, we invited individuals aged between 35 and 70 years who intended to live at their current address for at least another 4 years. Total physical activity was assessed using the International Physical Activity Questionnaire (IPQA). Participants with pre-existing CVD were excluded from the analyses. Mortality and CVD were recorded during a mean of 6·9 years of follow-up. Primary clinical outcomes during follow-up were mortality plus major CVD (CVD mortality, incident myocardial infarction, stroke, or heart failure), either as a composite or separately. The effects of physical activity on mortality and CVD were adjusted for sociodemographic factors and other risk factors taking into account household, community, and country clustering.

Randomized cluster crossover trials for reliable, efficient, comparative effectiveness testing: design of the Prevention of Arrhythmia Device Infection Trial (PADIT).

Randomized clinical trials are a major advance in clinical research methodology. However, there are myriad important questions about the effectiveness of treatments used in daily practice that are not informed by the results of randomized trials. This is in part because of important limitations inherent in the methodology of randomized efficacy trials which are performed with tight control of inclusion, exclusion, treatment, and follow-up. This approach enhances evaluation of clinical efficacy (performance in controlled situations) but increases complexity and is not well suited to test clinical effectiveness (performance under conditions of actual use). The cluster crossover trial is a new concept for efficient comparative effectiveness testing. Deep tissue infection occurs in 2% of patients after arrhythmia device implantation, usually requires system extraction, and increases mortality. There is variation in antibiotic prophylaxis used to reduce implanted device infections. To efficiently evaluate the comparative effectiveness of antibiotic strategies now in use, we designed a cluster crossover clinical trial, which randomized implanting centres to 1 of 2 prophylactic antibiotic strategies, which became the standard care at the centre for 6 months, followed by crossover to the other strategy, rerandomization, and second crossover. This method greatly reduces trial complexity because it aligns study procedures with usual clinical care and increases generalizability. Pilot studies have tested the feasibility and an 10,800-patient trial, funded by the Canadian Institutes of Health Research, is now under way. The cluster crossover randomized trial design is well suited to efficiently test comparative effectiveness of existing treatments where there is variability of practice, clinical equipoise, and minimal risk.

Efficacy and safety of enoxaparin compared with unfractionated heparin in the pharmacoinvasive management of acute ST-segment elevation myocardial infarction: Insights from the TRANSFER-AMI trial.

AIMS: An early invasive strategy after fibrinolysis for ST-elevation myocardial infarction (STEMI) improves outcomes, but the relative efficacy and safety of enoxaparin compared with unfractionated heparin (UFH) as part of this approach are unknown. METHODS AND RESULTS: In the TRANSFER-AMI trial, patients with high-risk STEMI received fibrinolysis and were then randomized to either standard treatment or to immediate transfer for coronary angiography. In this substudy, the outcome of patients aged <75 years treated with enoxaparin is compared with that of patients who received UFH. Logistic regression and propensity score models were used to evaluate the efficacy and safety of these anticoagulants. Enoxaparin was administered to 498 patients, and UFH, to 448 patients, at the time of fibrinolysis. Approximately 50% in each group were randomized to the early invasive strategy. The primary composite end point of death, reinfarction, recurrent ischemia, new or worsening heart failure, or cardiogenic shock at 30 days occurred in 11.9% and 11.6% of the patients who received enoxaparin and UFH, respectively (adjusted odds ratio 0.95 [95% CI 0.60-1.51], P = .84). Enoxaparin use was associated with more access site bleeding (5.0% vs 2.9%, P = .04) and mild bleeding (12.1% vs 7.8%, P = .03). CONCLUSIONS: Among high-risk patients with STEMI undergoing early or late transfer for cardiac catheterization after fibrinolysis, enoxaparin was associated with similar efficacy compared with UFH, but there was more minor bleeding with enoxaparin (ClinicalTrials.gov no. NCT00164190).

Relationship between risk stratification at admission and treatment effects of early invasive management following fibrinolysis: insights from the Trial of Routine ANgioplasty and Stenting After Fibrinolysis to Enhance Reperfusion in Acute Myocardial Infarction (TRANSFER-AMI).

AIMS: We sought to determine the effectiveness of early routine percutaneous coronary intervention (PCI) post-fibrinolysis for ST-elevation myocardial infarction (STEMI) in relation to baseline risk status. METHODS AND RESULTS: In this post hoc subgroup analysis of Trial of Routine Angioplasty and Stenting after Fibrinolysis to Enhance Reperfusion in Acute Myocardial Infarction (TRANSFER-AMI), we stratified 1059 STEMI patients receiving tenecteplase into low-intermediate [Global Registry of Acute Coronary Events (GRACE) risk score<155; n=889] vs. high-risk (GRACE risk score ≥155; n=170) groups, based on the GRACE risk score for in-hospital mortality. There was a significant interaction between treatment assignment and risk status for the composite endpoint of death/re-MI at 30 days (P for interaction<0.001). Compared with the standard treatment, pharmacoinvasive therapy (early routine PCI) was associated with a lower rate of death/re-MI at 30 days in the low-intermediate risk stratum (8.1 vs. 2.9%, P<0.001), but a higher rate of death/re-MI in the high-risk group (13.8 vs. 27.8%, P=0.025). We found similar heterogeneity in the treatment effects on 30-day mortality and death/re-MI at 1 year (P for interaction=0.008 and 0.001, respectively), when the GRACE risk score was analysed as a continuous variable (P for interaction<0.001) and when patients were stratified by the Thrombolysis In Myocardial Infarction (TIMI) risk score (P for interaction=0.001). CONCLUSION: We observed a strong heterogeneity in the treatment effects of a pharmacoinvasive strategy after fibrinolysis for STEMI, which is associated with improved outcomes only among patients with a low-intermediate GRACE risk score. Conversely, the early invasive strategy is associated with worse outcomes in high-risk patients. These novel findings should be considered exploratory only and require confirmation in other trials and meta-analyses. CLINICAL TRIAL REGISTRATION INFORMATION: http://www.clinicaltrials.gov/ct2/show/NCT00164190 ClinicalTrials.gov number, NCT00164190.

Relation between hemoglobin level and recurrent myocardial ischemia in acute coronary syndromes detected by continuous electrocardiographic monitoring.

Anemia has been associated with adverse outcomes in patients with acute coronary syndromes (ACS). However, the underlying pathophysiologic mechanisms have not been well elucidated. We sought to determine the independent relation between the hemoglobin level and recurrent ischemia in patients with non-ST-segment elevation ACS using continuous electrocardiographic monitoring. In the Integrilin and Enoxaparin Randomized Assessment of Acute Coronary Syndrome Treatment (INTERACT) trial, 746 patients presenting with non-ST-segment elevation ACS underwent continuous ST-segment monitoring for 48 hours. The data were analyzed independently at a core laboratory. We stratified the study population according to their hemoglobin level on presentation. The primary outcome of the study was recurrent ischemia, defined as ST-segment shifts on continuous electrocardiographic monitoring. Of the 705 patients with analyzable data, 64 had a baseline hemoglobin level <120 g/L, 259 had a level of 120 to 139 g/L, 315 had a level of 140 to 159 g/L, and 67 had a level >160 g/L. The corresponding rates of recurrent ischemia were 39.1%, 22.0%, 15.6%, and 11.9% (p for trend <0.001). A lower hemoglobin level was associated with advanced age, co-morbidities, and a higher GRACE risk score. In multivariable analysis adjusting for these confounders, lower hemoglobin levels retained a significant independent association with recurrent ischemia (p for trend = 0.004). In conclusion, a lower hemoglobin level at presentation was independently associated with recurrent ischemia detected by continuous electrocardiographic monitoring in the setting of non-ST-segment elevation ACS. This suggests that anemia might predispose patients to recurrent ischemia, which could be an important underlying mediator of worse outcomes in patients with lower hemoglobin levels.

Patient age, ethnicity, medical history, and risk factor profile, but not drug insurance coverage, predict successful attainment of glycemic targets: Time 2 Do More Quality Enhancement Research Initiative (T2DM QUERI).

OBJECTIVE: To identify factors in patients with type 2 diabetes and A1C >7.0% associated with attainment of A1C ≤ 7.0%. RESEARCH DESIGN AND METHODS: We used a prospective registry of 5,280 Canadian patients in primary care settings enrolled in a 12-month glycemic pharmacotherapy optimization strategy based on national guidelines. RESULTS: At close out, median A1C was 7.1% (vs. 7.8% at baseline) with 48% of subjects achieving A1C ≤ 7.0% (P < 0.0001). Older patients of Asian or black origin, those with longer diabetes duration, those with lower baseline A1C, BMI, LDL cholesterol, and blood pressure, and those on angiotensin receptor blockers and a lower number of antihyperglycemic agents, were more likely to achieve A1C ≤ 7.0% at some point during the study (all P < 0.0235). Access to private versus public drug coverage did not impact glycemic target realization. CONCLUSIONS: Patient demography, cardiometabolic health, and ongoing pharmacotherapy, but not access to private drug insurance coverage, contribute to the care gap in type 2 diabetes.

Treatment gaps in the management of cardiovascular risk factors in patients with type 2 diabetes in Canada.

OBJECTIVES: To evaluate vascular protection treatment patterns and attainment of the 2003 Canadian Diabetes Association's recommended targets in ambulatory patients with type 2 diabetes. METHODS: Between 2005 and 2006, 3002 outpatients with type 2 diabetes were enrolled by 229 primary health care settings across Canada. Baseline characteristics, therapeutic regimens and treatment success - defined as the achievement of a blood pressure (BP) of 13080 mmHg or lower, glycosylated hemoglobin (A1C) of 7% or lower, low-density lipoprotein cholesterol (LDL-C) lower than 2.5 mmolL and total cholesterolhigh-density lipoprotein cholesterol ratio lower than 4.0 - are reported. RESULTS: Overall, 46% of individuals had a BP that was above the Canadian Diabetes Association's recommended target. Of these, 11% were untreated, 28% were receiving monotherapy, 38% were not receiving an angiotensin-converting enzyme inhibitor and 16% were not receiving either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Optimal A1C levels were achieved in 53% of patients. Of those who did not attain A1C targets, 3% were not on glucose- lowering pharmacotherapy and 27% were receiving monotherapy. A total of 74% of patients were treated with statins. Overall, 64% and 62%, respectively, met the target LDL-C and the target total cholesterolhigh-density lipoprotein cholesterol ratio. Statins were not prescribed to 43% of patients with LDL-C above target. Antiplatelet therapy was implemented in 81% of patients. In total, 21% achieved the combined targets for BP, A1C and LDL-C. INTERPRETATION: A substantial proportion of patients did not achieve guideline-recommended targets and were not receiving evidence- based therapy for vascular protection two years after publication of the Canadian guidelines. More research is warranted, and novel and effective strategies must be tested and implemented to correct this ongoing treatment gap.

QRS prolongation in patients with acute coronary syndromes.

BACKGROUND: QRS prolongation with or without bundle branch block (BBB) has been associated with adverse outcome in myocardial infarction; we examined the relationship between QRS duration and outcome in a broad spectrum of patients with acute coronary syndrome (ACS). METHOD AND RESULTS: Core laboratory evaluation of the presenting electrocardiogram in Canadian ACS Registry patients (n = 5,003) showed 4,289 (85.7%) had QRS <120 milliseconds, 202 (4.0%) patients had QRS > or =120 milliseconds without BBB, 262 (5.2%) had left BBB (LBBB), and 250 (5.0%) had right BBB. Compared to patients with QRS <120 milliseconds, patients with QRS > or =120 milliseconds without BBB had higher in-hospital (3.5% vs 1.9%, odds ratio [OR] 1.87, 95% CI 0.85-4.09, P = .12) and 1-year mortality (14.9% vs 7.7%, OR 2.10, 95% CI 1.38-3.18, P = .001). In-hospital and 1-year mortality was significantly higher in patients with BBB (eg, LBBB compared with QRS <120 milliseconds) (5.0% vs 1.9%, OR 2.71, 95% CI 1.49-4.94, P = .001, and 23.8% vs 7.7%, OR 3.74, 95% CI 2.72-5.13, P < .001). Analyzed as a continuous variable and after adjustment for validated prognosticators, QRS duration was an independent predictor of 1-year death (OR 1.11, 95% CI 1.06-1.16, P < .001) and death/myocardial infarction (OR 1.06, 95% CI 1.02-1.11, P = .003). However, when using clinically applicable QRS duration evaluation, only LBBB was an independent predictor of 1-year mortality (OR 1.93, 95% CI 1.28-2.90, P = .002). CONCLUSIONS: In patients presenting with a broad spectrum of suspected ACS, QRS prolongation-particularly in the setting of LBBB-is an independent predictor of in-hospital and 1-year mortality.

Validation of the Global Registry of Acute Coronary Event (GRACE) risk score for in-hospital mortality in patients with acute coronary syndrome in Canada.

BACKGROUND: The Global Registry of Acute Coronary Event (GRACE) risk score was developed in a large multinational registry to predict in-hospital mortality across the broad spectrum of acute coronary syndromes (ACS). Because of the substantial regional variation and temporal changes in patient characteristics and management patterns, we sought to validate this risk score in a contemporary Canadian population with ACS. METHODS: The main GRACE and GRACE(2) registries are prospective, multicenter, observational studies of patients with ACS (June 1999 to December 2007). For each patient, we calculated the GRACE risk score and evaluated its discrimination and calibration by the c statistic and the Hosmer-Lemeshow goodness-of-fit test, respectively. To assess the impact of temporal changes in management on the GRACE risk score performance, we evaluated its discrimination and calibration after stratifying the study population into prespecified subgroups according to enrollment period, type of ACS, and whether the patient underwent coronary angiography or revascularization during index hospitalization. RESULTS: A total of 12,242 Canadian patients with ACS were included; the median GRACE risk score was 127 (25th and 75th percentiles were 103 and 157, respectively). Overall, the GRACE risk score demonstrated excellent discrimination (c statistic 0.84, 95% CI 0.82-0.86, P < .001) for in-hospital mortality. Similar results were seen in all the subgroups (all c statistics >/=0.8). However, calibration was suboptimal overall (Hosmer-Lemeshow P = .06) and in various subgroups. CONCLUSIONS: GRACE risk score is a valid and powerful predictor of adverse outcomes across the wide range of Canadian patients with ACS. Its excellent discrimination is maintained despite advances in management over time and is evident in all patient subgroups. However, the predicted probability of in-hospital mortality may require recalibration in the specific health care setting and with advancements in treatment.