Confidential: For Review Only - BMJ...Moman A.Mohammad1, Sofia Karlsson1, Jonathan Haddad1, Björn...

Confidential: For Review OnlyChristmas, national holidays, sport events and time factors as triggers of Acute Myocardial Infarction - A SWEDEHEART

observational study

Journal: BMJ

Manuscript ID BMJ.2018.046569.R1

Article Type: Christmas research

BMJ Journal: BMJ

Date Submitted by the Author: 21-Oct-2018

Complete List of Authors: Mohammad, Moman; Department of Cardiology, Clinical Sciences, Lund University, Lund, Sweden, Karlsson, Sofia; Department of Cardiology, Clinical Sciences, Lund University, Skane University Hospital, Lund, SwedenHaddad, Jonathan; Department of Cardiology, Clinical Sciences, Lund University, Skane University Hospital, Lund, SwedenCederberg, Björn; Department of Cardiology, Clinical Sciences, Lund University, Skane University Hospital, Lund, SwedenJernberg, Tomas; Clinical Sciences, Danderyd University Hospital, Karolinska Institutet, Stockholm, SwedenLindahl, Bertil; Department of Medical Sciences and Uppsala Clinical Research Center, Uppsala University, Uppsala, SwedenFrobert, Ole; Örebro University, Faculty of Health, Department of Cardiology, Örebro, SwedenKoul, Sasha; Department of Cardiology, Clinical Sciences, Lund University, Skane University Hospital, Lund, SwedenErlinge, David; Department of Cardiology, Clinical Sciences, Lund University, Skane University Hospital, Lund, Sweden

Keywords: Christmas, Myocardial infarction, Swedeheart, Sport, Time, External triggers, Holidays

https://mc.manuscriptcentral.com/bmj

BMJ


observational study

Moman A.Mohammad1, Sofia Karlsson1, Jonathan Haddad1, Björn Cederberg1, Tomas Jernberg2, Bertil Lindahl3, Ole Fröbert4, Sasha Koul1 and David Erlinge1

1. Department of Cardiology, Clinical Sciences, Lund University, Skane University Hospital, Lund, Sweden

2. Dept of clinical sciences, Danderyds University Hospital, Karolinska Institutet, Stockholm.

3. Department of Medical Sciences and Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden

4. Örebro University, Faculty of Health, Department of Cardiology, Örebro, Sweden

Word count: 2733

Correspondence to: David Erlinge, Department of Cardiology, Clinical Sciences, Lund

University, Skane University Hospital, Lund; 221 85 Lund, Sweden; telephone: +46 704 872194;

fax: +46 46 157857; email: [email protected].

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Confidential: For Review OnlySummary boxes

What is already known on this topic?

In western countries, cardiac mortality and hospital admission due to myocardial infarction has

been observed to peak on Christmas and New Years’ holiday. In addition, the risk of myocardial

infarction has also been linked to football championships; hurricanes and stock market crashes. It

is therefore conjectured that factors associated with emotional stress, physical activity and

lifestyle changes may modulate the onset of myocardial infarction by acting as short-term

triggers.

What this study adds

We investigated the risk of MI during national holidays, sports events and various time aspects

to identify times of hazard in a large study covering 16 years of clinical MI data. We observed

higher risk of MI during Christmas/New Years and Midsummer holidays but not during Easter

holiday. The highest risk was observed during Christmas Eve and in patients over 75 years,

patients with previous diabetes and coronary artery disease.

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Confidential: For Review OnlyChristmas holidays:

In Sweden, Christmas Eve on December 24th is the main day of Christmas festivities. The

celebrations continue on Christmas day and Boxing Day.

New Year holidays:

Whereas Christmas is celebrated with the immediate family, New Year’s Eve is generally

celebrated with friends. Besides excess food and drink intake, the festivities includes awaiting

midnight to share New Year’s resolutions and wish each other a happy new year under firework

lights.

Easter Holidays:

Easter celebration is the first long weekend after winter. Families and friends meet and eat with a

focus on eggs and children dress as Easter witches.

Midsummer Holiday:

Apart from Christmas, Midsummer is the most important holiday in Sweden. On the evening

preceding the summer solstice, Midsummer Eve, Swedes gather to celebrate by dancing around a

maypole, singing, eating and drinking often in excess. It is often associated with the Christian

holiday, the Feast Day of St John the Baptist on the 24th of June.

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Confidential: For Review OnlyObjectives

To study circadian rhythm aspects, national holidays and major sport events as triggers of

myocardial infarction (MI).

Design

Retrospective observational study using the nationwide coronary care unit registry,

SWEDEHEART.

Setting

Nationwide.

Participants

A total of 283,014 cases MI were reported to the registry between 1998-2013 and included in

this study. Symptom onset date was documented for all cases and time to nearest minute for

88.20%.

Interventions

All MIs with symptom onset on Christmas/New Years, Easter, Midsummer holiday were

identified. Similarly, we identified all MIs that occurred during a FIFA world cup, UEFA

EuroCup and winter and summer Olympic games. The two weeks before and after a holiday

were set as control period and for sport events the control period was set to the same time period

1 year before and after the tournament. Circadian and circaseptan analyses were performed with

Sunday and 00.00 as reference day and hour to which all other days and hours were compared.

Incidence rate ratios were calculated using a count regression model.

Main outcome measures

Daily count of MI.

Results

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Confidential: For Review Only

4

Christmas and Midsummer holidays were associated with higher risk of MI, (incidence rate ratio

(IRR)=1.15, 95% confidence interval (CI) [1.12-1.19], p<0.001) and (IRR=1.12, 95%CI [1.07-

1.18], p<0.001) respectively. The highest associated risk was observed for Christmas Eve

(IRR=1,37, 95%CI [1,29-1,46], p<0.001). No increased risk was observed during Easter holiday

or sport events. A circaseptan and circadian variation in risk of MI was observed with higher risk

during early mornings and on Mondays. Results were most pronounced in older and sicker

patients.

Conclusions

In this nationwide real-world study covering 16 years of MI hospitalizations with symptom

onset documented to nearest minute, Christmas and Midsummer holidays were associated with

higher risk of MI particularly in older and sicker patients, suggesting a role of external triggers

in vulnerable patients.

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Confidential: For Review OnlyIntroduction

Ischemic heart disease, although declining in high income countries, remains the most common

cause of morbidity and mortality worldwide.1 Current understanding is that this disease is

multifactorial with predisposing modifiable and non-modifiable risk factors1-3. However, studies

have also shown that external factors may be involved in triggering the onset of myocardial

infarction (MI) by contributing in eliciting the rupture of unstable plaques, leading to MI. These

short-term risk factors include, but are not limited to, emotional stress, heavy physical activity

and cold weather exposure as well as air pollution3-11. Moreover, Muller et al. presented the

variation in MI incidence peaking at 9 AM and the circadian variation in MI with daily activities

increasing the risk of coronary thrombosis and MI through hemodynamic and vasoconstrictive

forces12,13. Goldberg et al. and Rocco et al. further expanded this view by adjusting for time of

waking up and both groups could show the risk of MI to be increased during the first 1-4 hours

after awakening14,15.

A number of these short-term potential triggers, ranging from earthquakes, hurricanes, wars,

sports events to stock market volatility have repeatedly been associated with a higher risk of

MI16-20. Furthermore, prior studies have shown a peak in cardiac mortality in the western world

on Christmas day, New Years’ day and during Islamic holidays in countries where this religion is

predominating21-24. Even Sir Winston Churchill was thought to have suffered from a heart attack

when visiting the White House at Christmas 194125. However, most previous studies have used

surrogate variables such as MI mortality, ambulance records, death certificates, and

administrative data including International Classification of Diseases (ICD) -codes as indicators

of MI and as such may introduce bias through misclassification and uncertainties in time of

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symptom onset. Thus, there is a lack of more granular data with exact time of symptom onset as

well as severity and type of MI in a nationwide setting.

We hypothesized that short-term risk factors may be associated with risk of MI. Furthermore; we

hypothesized that the potential risk may differ with regard to ECG subtypes of MI; ST-elevation

MI (STEMI) and non ST-elevation MI (NSTEMI). Our objective was therefore to study national

holidays, major sport events as well as circadian rhythm aspects as triggers of ECG and

biomarker positive myocardial infarctions with high-resolution data on symptom onset

documented to the nearest minute, in a large nationwide setting.

Methods

Study population

The prospective nationwide Swedish Web System for Enhancement and Development of

Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies

(SWEDEHEART) registry was used to identify cases of MI in Sweden between 1998-2013. The

SWEDEHEART registry has been described in details elsewhere; briefly, all patients with

symptoms of an acute coronary syndrome admitted to a coronary care unit or other specialized

facility in Sweden are enrolled26. The registry prospectively collects information on background

characteristics such as age, body mass index, smoking status, electrocardiographic findings as

well as other examinations, interventions, complications, laboratory measures, discharge

medications and diagnoses. The diagnosis of MI including subtypes is set based by the treating

physician’s assessment of patient at discharge. The date and time of symptom onset is

documented to the nearest minute and was used as the main variable in this study. All cases of

MI reported to the SWEDEHEART registry during the study period were included in this study.

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Study design

All cases of MI with symptom onset on Christmas/New Years, Easter, and Midsummer holiday

were identified. Christmas/New Years holidays were defined as Christmas Eve, Christmas day,

Boxing Day, New Year’s Eve, New Year’s Day and the Epiphany. Easter holiday was defined as

Good Friday, Easter Eve, Easter Day and Easter Monday. Midsummer Eve and Midsummer Day

(also known as St John’s Day) constituted Midsummer holiday. Similarly, we identified all MIs

that occurred on all Fédération Internationale de Football Association (FIFA) world cup, Union

of European Football Association (UEFA) Euro Cup and winter and summer Olympic games

during the study period. The two weeks before and after a holiday was set as control period and

for sport events the control period was set to the same time period 1 year before and after the

tournament. Circadian and circaseptan analyses were performed with Sunday and 00.00 as the

reference day and hour to which all other days and hours were compared. The primary outcome

was daily count of MI, with STEMI and NSTEMI studied independently as secondary outcome

measures. Incidence rate ratios were calculated comparing incidence rates of a period/time of

interest to a control period according to the statistical analysis section. Pre-specified subgroup

analyses were assessed for all periods of interest. These subgroups were based on sex, age ≥75

years vs. age <75 years, smoking status, diabetes, hypertension, coronary artery disease (CAD)

as well as patients on medications such as beta-blockers, calcium inhibitors, aspirin, angiotensin

converting enzyme inhibitors/angiotensin receptor blockers (ACE-I/ARB) and statins. This study

was approved by Lund University's ethical Committee (2015/297). A sensitivity analysis

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addressing the risk of MI on days involving the Swedish soccer team during FIFA world cup and

UEFA Euro Cup was conducted. In addition, sensitivity analyses adjusted for year as a

categorical variable were conducted to control for time trends in MI during the study period.

Statistical methods

Continuous variables are displayed as mean ± standard deviation. Categorical variables are

displayed as counts and percentages. Chi-square test was used to assess statistical significance

between categorical variables. Incidence rate ratios were calculated for major holidays, sport

events and day of the week as well as for hour of symptom onset by using a Poisson regression

model. Calendar week was plotted with a line graph to assess seasonality. All analyses were

conducted on complete case data and only two variables contained missing data exceeding 1%.

These were time of symptom onset and smoking status with 11.80% and 8.50% missing data

respectively. Family-wise error rate was applied within strata (total MI, NSTEMI and STEMI)

using the Hochberg method to control for type 1 errors owing to multiple testing. All statistical

analyses were performed using STATA version 14.1 for Macintosh, StataCorp, Texas, USA). A

two-sided p-value <0.05 was considered statistically significant.

Results

Patient characteristics

A total of 283,014 admissions of MI during the study period and all were included in the study.

Baseline demographics are presented in Table 1 and a total of 95,176 patients had STEMI at

admission. Patients with STEMI were on average 4 years younger, more frequently men and

current smokers compared to patients with NSTEMI.

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Major holidays

A higher risk of MI was observed for Christmas day, Boxing Day and New Years’ day but not

for New Years’ Eve and Epiphany. During Christmas/New Years holiday there was a 15%

higher risk of MI (incidence rate ratio (IRR)) =1.15 95% CI [1.12-1.19], p=<0.001). MI risk at

Christmas eve was higher than the other individual days of the holiday (IRR =1.37 95% CI

[1.29-1.46], p=<0.001) and the risk was even higher after ECG stratification of MI, risk of

NSTEMI (IRR =1.48 95%CI [1.38-1.59], p=<0.001). Easter holiday was not associated with a

higher IRR of MI while Midsummer holiday was associated with a higher risk, (IRR =1.12

95%CI [1.07-1.18], p=0.001) largely driven by NSTEMI (IRR =1.16 95%CI [1.09-1.23],

p<0.001).

Sports events

During the study period, 4 FIFA world cups and 4 European Football championships took place.

Sports events were not associated with a higher incidence of total MI, NSTEMI or STEMI,

although a trend was observed for summer Olympic games in men, but this did not reach

statistical significance after adjusting for multiple testing Table 1 and Supplementary Table 2.

Time aspects

A significant circaseptan variation in incidence of MI was observed on Mondays, also evident

after stratification into NSTEMI and STEMI, Figure 2. A clear and significantly higher incidence

of MI was observed in the analysis of hour of symptom onset, peaking at 8 AM, most prominent

for NSTEMI, Figure 2 and Supplementary Table 1.

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Subgroup and sensitivity analyses

Consistent results were observed for all subgroups with higher IRR of MI during Christmas

holiday except for the subgroup of current smokers, Supplementary Figure 1 and Supplementary

Table 2. The risk was higher in patient’s aged ≥75 years, patients with previous diabetes and

patients with previous CAD. No subgroup was particularly more affected on Easter holidays but

a statistically non-significant trend towards higher risk of MI in men during midsummer was

seen. Consistent results with higher risk of MI on Mondays were seen in all subgroups except for

current smokers Supplementary Figure 3 and Supplementary Table 2. Consistent results for hour

of symptom onset were observed in all subgroups, Supplementary Figure 4 and Supplementary

Table 2. An analysis of Christmas and Midsummer holidays was done for all patients that

underwent coronary angiography with subsequent revascularization with percutaneous coronary

intervention (PCI) or coronary artery bypass grafting (CABG) vs. patients that underwent

coronary angiography with no revascularization performed. The associated higher risk of MI

during these holidays was limited to MIs that did not undergo revascularization therapy,

Supplementary Figure 2. No associated risk was observed in the sensitivity analyses exploring

only the days when Sweden played in FIFA world cup or UEFA Euro cup. The sensitivity

analyses controlling for long-term trends in MI resulted in consistent results.

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Confidential: For Review OnlyDiscussion


using data on date and time of symptom onset, documented to the nearest minute in a large

nationwide setting with 16 years of MI data. We observed higher risk of MI during

Christmas/New Years and Midsummer holidays but not during Easter holiday. Sports events

were not associated with higher risk of MI. We observed a prominent peak incidence on

calendar week 52, Mondays and at 8 AM. This is to our knowledge the largest study utilizing

electrocardiographic and biomarker positive MI from a well-known registry. These results are

in line with studies using administrative data.

Major Holidays

We observed a remarkable 37% higher risk of MI during Christmas Eve alone compared to the

control period, by far the individual day with the highest risk of MI. Previous meta-analyses of

short-term triggers such as acute experience of anger, anxiety, sadness, grief and stress increase

MI risk, possibly explaining the higher associated risk in our study4,9. Although holiday

celebrations should be associated with the opposite, this may not be the case for all individuals.

The association of higher risk on Christmas was more pronounced in patients over 75 years,

patients with previous diabetes and patients with previous coronary artery disease highlights the

need for the medical society to raise awareness of this fragile patient group during this holiday.

These findings warrant further research to identify the mechanisms behind this phenomenon.

Understanding what factors, activities and emotions precede these MIs and how they differ from

MIs suffered on other days could result in a method to cope with this and ultimately a lesser

cardiovascular burden on society. It could be argued that relatives visiting their dear ones after a

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long time apart find them in a less than good general condition and decide to admit them to a

hospital. However, this should be followed by a decline in number of MIs the weeks after

Christmas compared to the weeks preceding Christmas. Similarly, a healthcare seeking delay

caused by patients’ unwillingness to disrupt the on-going celebration should be preceded by

lower rates of MI before Christmas as compared to after Christmas. In other words, the absence

of any decline preceding or following Christmas indicates that these behavioural aspects are not

the main contributing factors behind the Christmas peak of MI.

New Years’ eve is usually associated with the New Years’ celebrations in Sweden.

However, no associated risk was observed in our study but instead, we observed a higher risk on

New Years day, possibly explained by a negligence and masking of symptoms due to alcohol

resulting in healthcare seeking delay. The associated risk of MI during holidays was similar

between men and women except for Midsummer, which was associated with a higher risk in men

only. Men may expose themselves to risk factors like smoking, drinking and overeating to a

higher extent during this holiday and although no sex-specific statistics are available, alcohol

sale statistics from the government-owned monopoly chain of retail stores shows peaking sales

on Christmas and Midsummer27.

Time aspects

We confirm previous studies using administrative data and circadian and circaseptan variation in

MI12,14,28,29. The incidence of MI peaked on calendar week 52, on Mondays and around 8 AM.

The rate of STEMI had a normal, lightly skewed distribution whereas NSTEMI ran a more

fluctuating course over the day (Figure 2). Mondays were associated with the highest risk of MI

and differences were observed between STEMI and NSTEMI. Whereas risk of NSTEMI

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remained higher during weekdays compared to weekends, no other day of week was associated

with higher or lower risk of STEMI. However, behavioural aspect with healthcare-seeking delay

due to opening hours cannot be ruled out30. Although we used symptom onset and not admission

date, healthcare-seeking delay may still confound results, as symptom onset may be less defined

in patients with NSTEMI. The decline in incidence rate of NSTEMI on weekends and at night is

supportive of this, in contrast to STEMI, usually presenting with a more pronounced

symptomatology and minimal healthcare delay. Previous studies have shown a higher risk of MI

primarily allocated to the working population29. In contrast, we found similar patterns in retired

patients (≥75 years) as for younger patients (<75 years). Previously proposed explanation to the

circaseptan peak in MI include stressful Mondays and a rise in arterial blood pressure and heart

rate, peak cortisol and increased blood viscosity and platelet aggregability in the morning hours

may alone or in combination, explain the circadian variation.13

Sports events

Sports event periods were not associated with a higher risk of MI, which was in contrary to our

expectations with regard to previous studies17,31. Wilbert-Lampen et al. presented an increased

incidence in MI in Greater München area during FIFA world cup in Germany 2006. A number of

aspects may contribute to the discrepancy in results. First of all, the fact that Germany was the

host of the tournament might infer involvement in the sport even by non-dedicated fans. In

addition, the associated risk was restricted to days involving the German soccer team and highest

during the day of the quarter and semi-finals. There was a complete lack of risk on the day the

German team played for third place and, the only day that was associated with a higher risk and

not involving the German team was the final. Altogether, these factors indicate that a stronger

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emotional stress may be required to trigger MI. We tried to address this in our sensitivity

analysis of days involving the Swedish team playing which did not show any associated risk.

Moreover, no subgroup suffered a higher risk of MI during any sport periods that were studied

thus normal watching sport events can be considered safe.

Pathophysiological aspects

We were able to characterize MI to a higher degree than previously and this allowed us to study

STEMI and NSTEMI independently together with a wide range of subgroups. Our results

showed consistently higher risk of MI due to higher rates of NSTEMI, elderly patients and

patients with previous diabetes, hypertension, coronary artery disease and those on previous

medications with regard to all studied potential triggers, highlighting the concept of vulnerable

patients. Whereas the current understanding of vulnerable plaques is that it is a local process of a

systemic disease (atherosclerosis), the concept of the vulnerable patients is broader, involving

blood vulnerable to thrombosis and myocardium vulnerable to arrhythmias among other risk

factors32. It cannot be ruled out that activities and emotions associated with holiday’s results in

myocardial infarction secondary to ischemia due to an increased oxygen demand in elder and

sicker patients. This is supported by the subgroup analysis on Christmas and New Years’ holiday

(Supplementary Figure 2) that showed an incremental risk increase of MI with each age quartile

in addition to the lack of risk of STEMI, as type 2 infarctions generally do not present as

STEMI33. However, infarct type classification was not introduced in the SWEDEHEART

registry until 2010 and in order to address this topic; we conducted a post hoc analysis of risk of

MI resulting in a coronary angiography between 2004-2013. Neither Christmas nor Midsummer

holiday were associated with risk of an MI resulting in revascularization; these holidays were

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rather associated with MI in which PCI or surgery was not deemed necessary. This suggests that

a large proportion of MI with non-occlusive coronary arteries may account for the higher risk of

MI during these holidays. Although this post hoc analysis did not take into account chronic total

occlusions or distal occlusions that were left untreated by the interventionist, these findings

warrant further investigation.

The rationale behind our subgroup analyses i.e. patients on previous medications was to

investigate possible inhibitory mechanisms of certain pharmacotherapies on the mechanisms of

the short term triggers of MI. Medications lowering heart rate, reducing blood pressure, lipids

and platelet aggregation might reduce plaque vulnerability to external triggers. For example,

beta-adrenergic inhibitors have been shown to blunt the circadian variation in MI by reducing

heart rate and blood pressure and increase coronary blood flow by prolonging diastole.34

However, in our study, patients on cardiovascular medications had similar or higher risk of MI

during holidays, our explanation to this is thus in line with our main theory - the medications

are surrogate measures of a sicker population, more vulnerable to external triggers. On the

contrary, the subgroup analyses of circadian variation were rather associated with lower risk,

Supplementary figure 4, in line with previous studies suggesting that these medications partially

blunting the mechanisms of short-term triggers of MI.

Limitations

Due to the nature of this study as an observational study, causality cannot be determined, as

unobserved confounders cannot be ruled out. Previous publications have shown a higher

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incidence of MI during colder temperatures. However, it is unlikely that national holidays should

be associated with lower temperature to bias the results since control periods two weeks before

and after holidays were used.

Conclusion



higher risk of MI. Consistently, we observed a higher risk in older and sicker patients,

suggesting a role of external triggers in the vulnerable patients.

Conflicts of interest

None of the authors have anything to disclose.

Funding

This work was supported by The Swedish Heart and Lung Foundation, Swedish Scientific

Research Council, SSF (TOTAL-AMI), Knut and Alice Wallenberg Foundation, ALF and Skane

University Hospital funds.

Acknowledgment

The authors would like to thank the staff members at all coronary care units in Sweden for their

help and cooperation in contributing data to the Swedish Web-system for Enhancement and

Development of Evidence-based care in Heart disease Evaluated According to Recommended

Therapies (SWEDEHEART) system. The sponsors had no involvement in the study design,

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collection, analysis or interpretation of data or writing of the manuscript or in the decision to

submit manuscript for publication.

Transparency Statement

M.A.Mohammad affirms that this manuscript is an honest, accurate, and transparent account of

the study being reported; that no important aspects of the study have been omitted; and that any

discrepancies from the study as planned (and, if relevant, registered) have been explained.

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Confidential: For Review OnlyReferences:

1. WHO. World health statistics - Monitoring health for the SDGs, Sustainable Development Goals. Geneva: World Health Organization; 2017. Licence: CC BY-NC-SA 3.0 IGO. 2017.2. Yusuf S, Reddy S, Ounpuu S, Anand S. Global burden of cardiovascular diseases: part I: general considerations, the epidemiologic transition, risk factors, and impact of urbanization. Circulation 2001;104:2746-2753.3. Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F, McQueen M, Budaj A, Pais P, Varigos J, Lisheng L, Investigators IS. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet (London, England) 2004;364:937-952.4. Culic V, Eterovic D, Miric D. Meta-analysis of possible external triggers of acute myocardial infarction. Int J Cardiol 2005;99:1-8.5. Kwong JC, Schwartz KL, Campitelli MA, Chung H, Crowcroft NS, Karnauchow T, Katz K, Ko DT, McGeer AJ, McNally D, Richardson DC, Rosella LC, Simor A, Smieja M, Zahariadis G, Gubbay JB. Acute Myocardial Infarction after Laboratory-Confirmed Influenza Infection. N Engl J Med 2018;378:345-353.6. Barnes M, Heywood AE, Mahimbo A, Rahman B, Newall AT, Macintyre CR. Acute myocardial infarction and influenza: a meta-analysis of case-control studies. Heart 2015;101:1738-1747.7. Claeys MJ, Coenen S, Colpaert C, Bilcke J, Beutels P, Wouters K, Legrand V, Van Damme P, Vrints C. Environmental triggers of acute myocardial infarction: results of a nationwide multiple-factorial population study. Acta Cardiol 2015;70:693-701.8. Mustafic H, Jabre P, Caussin C, Murad MH, Escolano S, Tafflet M, Perier MC, Marijon E, Vernerey D, Empana JP, Jouven X. Main air pollutants and myocardial infarction: a systematic review and meta-analysis. JAMA 2012;307:713-721.9. Nawrot TS, Perez L, Kunzli N, Munters E, Nemery B. Public health importance of triggers of myocardial infarction: a comparative risk assessment. Lancet (London, England) 2011;377:732-740.10. Rosengren A, Hawken S, Ounpuu S, Sliwa K, Zubaid M, Almahmeed WA, Blackett KN, Sitthi-amorn C, Sato H, Yusuf S, investigators I. Association of psychosocial risk factors with risk of acute myocardial infarction in 11119 cases and 13648 controls from 52 countries (the INTERHEART study): case-control study. Lancet (London, England) 2004;364:953-962.11. Smyth A, O'Donnell M, Lamelas P, Teo K, Rangarajan S, Yusuf S, Investigators I. Physical Activity and Anger or Emotional Upset as Triggers of Acute Myocardial Infarction: The INTERHEART Study. Circulation 2016;134:1059-1067.12. Muller JE, Stone PH, Turi ZG, Rutherford JD, Czeisler CA, Parker C, Poole WK, Passamani E, Roberts R, Robertson T, et al. Circadian variation in the frequency of onset of acute myocardial infarction. N Engl J Med 1985;313:1315-1322.13. Muller JE, Tofler GH, Stone PH. Circadian variation and triggers of onset of acute cardiovascular disease. Circulation 1989;79:733-743.14. Goldberg RJ, Brady P, Muller JE, Chen ZY, de Groot M, Zonneveld P, Dalen JE. Time of onset of symptoms of acute myocardial infarction. Am J Cardiol 1990;66:140-144.15. Rocco MB, Barry J, Campbell S, Nabel E, Cook EF, Goldman L, Selwyn AP. Circadian variation of transient myocardial ischemia in patients with coronary artery disease. Circulation 1987;75:395-400.

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16. Ma W, Chen H, Jiang L, Song G, Kan H. Stock volatility as a risk factor for coronary heart disease death. Eur Heart J 2011;32:1006-1011.17. Wilbert-Lampen U, Leistner D, Greven S, Pohl T, Sper S, Volker C, Guthlin D, Plasse A, Knez A, Kuchenhoff H, Steinbeck G. Cardiovascular events during World Cup soccer. N Engl J Med 2008;358:475-483.18. Jiao Z, Kakoulides SV, Moscona J, Whittier J, Srivastav S, Delafontaine P, Irimpen A. Effect of Hurricane Katrina on incidence of acute myocardial infarction in New Orleans three years after the storm. Am J Cardiol 2012;109:502-505.19. Kloner RA, Leor J, Poole WK, Perritt R. Population-based analysis of the effect of the Northridge Earthquake on cardiac death in Los Angeles County, California. J Am Coll Cardiol 1997;30:1174-1180.20. Meisel SR, Kutz I, Dayan KI, Pauzner H, Chetboun I, Arbel Y, David D. Effect of Iraqi missile war on incidence of acute myocardial infarction and sudden death in Israeli civilians. Lancet (London, England) 1991;338:660-661.21. Zubaid M, Thalib L, Suresh CG. Incidence of acute myocardial infarction during Islamic holiday seasons. Eur J Epidemiol 2006;21:191-195.22. Phillips DP, Jarvinen JR, Abramson IS, Phillips RR. Cardiac mortality is higher around Christmas and New Year's than at any other time: the holidays as a risk factor for death. Circulation 2004;110:3781-3788.23. Phillips D, Barker GE, Brewer KM. Christmas and New Year as risk factors for death. Soc Sci Med 2010;71:1463-1471.24. Knight J, Schilling C, Barnett A, Jackson R, Clarke P. Revisiting the "Christmas Holiday Effect" in the Southern Hemisphere. Journal of the American Heart Association 2016;5.25. Vale JA, Scadding JW. Did Winston Churchill suffer a myocardial infarction in the White House at Christmas 1941? J R Soc Med 2017;110:483-492.26. Jernberg T, Attebring MF, Hambraeus K, Ivert T, James S, Jeppsson A, Lagerqvist B, Lindahl B, Stenestrand U, Wallentin L. The Swedish Web-system for enhancement and development of evidence-based care in heart disease evaluated according to recommended therapies (SWEDEHEART). Heart 2010;96:1617-1621.27. Systembolaget. Forsaljningsstatistik. https://www.omsystembolaget.se/om-systembolaget/foretagsfakta/forsaljningsstatistik/ (April 28, 2018).28. Spencer FA, Goldberg RJ, Becker RC, Gore JM. Seasonal distribution of acute myocardial infarction in the second National Registry of Myocardial Infarction. J Am Coll Cardiol 1998;31:1226-1233.29. Willich SN, Lowel H, Lewis M, Hormann A, Arntz HR, Keil U. Weekly variation of acute myocardial infarction. Increased Monday risk in the working population. Circulation 1994;90:87-93.30. Murakami S, Otsuka K, Kubo Y, Shinagawa M, Yamanaka T, Ohkawa S, Kitaura Y. Repeated ambulatory monitoring reveals a Monday morning surge in blood pressure in a community-dwelling population. Am J Hypertens 2004;17:1179-1183.31. Witte DR, Bots ML, Hoes AW, Grobbee DE. Cardiovascular mortality in Dutch men during 1996 European football championship: longitudinal population study. BMJ 2000;321:1552-1554.32. Naghavi M, Libby P, Falk E, Casscells SW, Litovsky S, Rumberger J, Badimon JJ, Stefanadis C, Moreno P, Pasterkamp G, Fayad Z, Stone PH, Waxman S, Raggi P, Madjid M, Zarrabi A, Burke A, Yuan C, Fitzgerald PJ, Siscovick DS, de Korte CL, Aikawa M, Juhani Airaksinen KE, Assmann G, Becker CR, Chesebro JH, Farb A, Galis ZS, Jackson C, Jang IK,

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Koenig W, Lodder RA, March K, Demirovic J, Navab M, Priori SG, Rekhter MD, Bahr R, Grundy SM, Mehran R, Colombo A, Boerwinkle E, Ballantyne C, Insull W, Jr., Schwartz RS, Vogel R, Serruys PW, Hansson GK, Faxon DP, Kaul S, Drexler H, Greenland P, Muller JE, Virmani R, Ridker PM, Zipes DP, Shah PK, Willerson JT. From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part I. Circulation 2003;108:1664-1672.33. Baron T, Hambraeus K, Sundstrom J, Erlinge D, Jernberg T, Lindahl B, group T-As. Type 2 myocardial infarction in clinical practice. Heart 2015;101:101-106.34. Willich SN, Linderer T, Wegscheider K, Leizorovicz A, Alamercery I, Schroder R. Increased morning incidence of myocardial infarction in the ISAM Study: absence with prior beta-adrenergic blockade. ISAM Study Group. Circulation 1989;80:853-858.

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Confidential: For Review OnlyTable 1. Baseline demographics. Total MI STEMI NSTEMI

283014 95176 187838

Age (years) 71.7 ± 12.2 69.1 ± 12.5 73.0 ± 11.8

Men 180205 (63.67%) 63119 (66.32%) 117086 (62.33%)

Women 102809 (36.33%) 32057 (33.68%) 70752 (37.67%)

BMI 26.7 ± 5.9 26.6 ± 7.1 26.8 ± 5.2

E-GFR 68.2 ± 24.1 73,4 ± 23.1 65.8 ± 24.2

Current Smoker 55673 (19.67%) 24531 (25.77%) 31142 (16.58%)

Medical history

Diabetes 61955 (21.89%) 15806 (16.61%) 46149 (24.57%)

Hypertension 123436 (43.61%) 36306 (38.15%) 87130 (46.39%)

Coronary Artery Disease 100638 (35.56%) 21280 (22.36%) 79358 (42.25%)

MI 91283 (32.25%) 19345 (20.33%) 71938 (38.30%)

PCI 32846 (11.61%) 7574 (7.96%) 25272 (13.45%)

CABG 23971 (8.47%) 3711 (3.90%) 20260 (10.79)

Chronic heart failure 3373 (1.19%) 573 (0.60%) 2800 (1.49%)

Stroke 17116 (6.05%) 3935 (4.13%) 13181 (7.02%)

Medication at admittance

Beta-blockers 120904 (42.72%) 29851 (31.36%) 91053 (48.47%)

Calcium antagonist 51107 (18.06%) 13603 (14.29%) 37504 (19.97%)

Aspirin 123647 (43.69%) 29258 (30.74%) 94389 (50.25%)

ACE-I/ARB 88592 (31.30%) 20955 (22.02%) 67637 (36.01%)

Statins 75381 (26.64%) 16978 (17.84%) 58403 (31.09%)

Diuretics 87367 (30.87%) 19180 (20.15%) 68187 (36.30%)

Table 1. Baseline demographics for the study population

ACE-I/ARB= Angiotensin converting enzyme inhibitor/angiotensin receptor blocker; BMI=Body Mass Index;

CABG=coronary artery bypass graft; E-GFR=estimated glomerular filtration rate; MI=myocardial infarction;

NSTEMI= non ST-Elevation MI; PCI= percutaneous coronary

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Confidential: For Review OnlyTable 2. Results.

FIFA= Fédération Internationale de Football Association. All P-values are adjusted for multiple testing.

*=p<0.05

Table 2. Results. Total MI Non ST-Elevation MI ST-Elevation MIPeriod of Interest

ControlPeriod

Period of Interest

ControlPeriod

Period of Interest

ControlPeriod

Holidays IR/day IR/day IRR (95%CI) IR/day IR/day IRR (95%CI) IR/day IR/day IRR (95%CI)Christmas/New Year 57.9 50.3 1.15 (1.12-1.19)*** 40.1 33 1.22 (1.17-1.26)*** 17.8 17.3 1.03 (0.98-1.09)Christmas Eve 69.1 50.3 1.37 (1.29-1.46)*** 48.9 33 1.48 (1.38-1.59)*** 20.2 17.3 1.17 (1.05-1.31)Christmas Day 64.9 50.3 1.29 (1.21-1.38)*** 46.6 33 1.41 (1.31-1.52)*** 18.3 17.3 1.06 (0.95-1.19)Boxing Day 61.1 50.3 1.21 (1.14-1.3)*** 41.2 33 1.25 (1.15-1.35)*** 19.9 17.3 1.15 (1.03-1.29)New Years Eve 46.3 50.3 0.92 (0.86-0.99) 31.1 33 0.94 (0.86-1.03) 15.2 17.3 0.88 (0.78-1)New Years Day 60.4 50.3 1.2 (1.12-1.28)*** 43.1 33 1.3 (1.21-1.41)*** 17.3 17.3 1 (0.89-1.13)Epiphany 46 50.3 0.92 (0.85-0.99) 29.9 33 0.91 (0.83-0.99) 16.1 17.3 0.93 (0.82-1.06)Easter Holidays 52.5 50.3 1.04 (1.01-1.08) 35 33.6 1.04 (1-1.09) 17.5 16.7 1.05 (0.99-1.12)Good Friday 50.9 50.3 1.01 (0.94-1.09) 32.1 33.6 0.96 (0.88-1.04) 18.8 16.7 1.13 (1.01-1.27)Easter Eve 51.9 50.3 1.03 (0.96-1.11) 35.3 33.6 1.05 (0.97-1.14) 16.6 16.7 1 (0.88-1.13)Easter Day 55.1 50.3 1.1 (1.03-1.17) 37.1 33.6 1.11 (1.02-1.2) 18 16.7 1.08 (0.96-1.21)Easter Monday 52.2 50.3 1.04 (0.97-1.11) 35.6 33.6 1.06 (0.97-1.15) 16.6 16.7 0.99 (0.88-1.12)Midsummer holidays 51.9 46.2 1.12 (1.07-1.18)** 35.3 30.4 1.16 (1.09-1.23)** 16.6 15.8 1.05 (0.96-1.15)Sport periods UEFA Euro Cup 47.3 46.9 1.01 (0.97-1.04) 31 31.1 1 (0.95-1.04) 16.3 15.8 1.03 (0.97-1.09)FIFA World Cup 45.2 46.2 0.98 (0.95-1.01) 29.8 30.7 0.97 (0.93-1.01) 15.4 15.5 0.99 (0.94-1.05)Winter Olympic Games 48.2 50 0.96 (0.92-1.01) 31.6 32.7 0.97 (0.92-1.02) 16.6 17.3 0.96 (0.89-1.03)Summer Olympic Games 47.4 45.6 1.04 (1-1.08) 31.6 30.4 1.04 (0.99-1.1) 15.8 15.2 1.04 (0.96-1.12)

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*p<0.01

*p<0.001

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Confidential: For Review OnlyFigure 1. Results of national holidays and week of symptom onset.

Shown are the associated risks of all MI, ST-elevation MI and Non ST-Elevation MI expressed

as incidence rate ratios for all major national holidays. Christmas/New Years include Christmas

Eve, Christmas Day, Boxing Day, New Years Eve and day as well as the Epiphany. Easter

holiday includes Good Friday, Easter Eve and Day and Easter Monday. P-values after

adjustment for multiple testing are presented in Table 2. Lower figure visualize the total number

of infarctions by calendar week, peaking on calendar week 52.

Figure 2. Results of day of week and hour of symptom onset.

Shown are the associated risks of overall MI, ST-elevation MI and Non ST-Elevation MI and

days of the week and hour of symptom onset expressed as incidence rate ratios. Reference period

for day of week is Sunday and reference hour for hour of symptom onset is 00:00. Hours are

defined as the hour of symptom onset, i.e. 00:00 - 00:59. P-values after adjustment for multiple

testing are presented in Supplementary Table 1.

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Confidential: For Review OnlySUPPLEMENTARY FIGURES

Supplementary Figure 1. Subgroup analyses.

Shown are the associated risks overall MI in various subgroups and major national holidays

expressed as incidence rate ratios. Christmas/New years include Christmas Eve, Christmas Day,

Boxing Day, New Years Eve and Day as well as the epiphany. Easter holiday includes Good

Friday, Easter Eve and Day and Easter Monday. P-value<0.05 for all bars not crossing the red

line. P-values after adjustment for multiple testing are presented in Supplementary Table 1.

Supplementary Figure 2. Additional subgroup analyses.

Left figure shows the associated risk of holidays on MI requiring revascularization after coronary

angiography was performed vs. those who did not undergo PCI/CABG. Right figure shows the

associated risk of MI on Christmas/New Years’ holiday for each age quartile. Christmas/New

Years’ include Christmas Eve, Christmas Day, Boxing Day, New Years’ Eve and Day as well as

the epiphany. P-value<0.05 for all bars not crossing the red line.

Suppementary Figure 3. Subgroup analyses of day of week.

Shown are the associated risks overall MI in various subgroups and day of week expressed as

incidence rate ratio. Reference period for day of week is Sunday and reference hour for hour of

symptom onset is 00:00. P-values after adjustment for multiple testing are presented in

Supplementary Table 1.

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Suppementary Figure 4. Subgroup analyses of hour of symptom onset

Shown are the associated risks overall MI in various subgroups and hour of symptom onset

expressed as incidence rate ratios. Reference period is 00:00. P-values after adjustment for

multiple testing are presented in Supplementary Table 1.

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observational study

Moman A.Mohammad1, Sofia Karlsson1, Jonathan Haddad1, Björn Cederberg1, Tomas Jernberg2, Bertil Lindahl3, Ole Fröbert4, Sasha Koul1 and David Erlinge1

1. Department of Cardiology, Clinical Sciences, Lund University, Skane University Hospital, Lund, Sweden

2. Dept of clinical sciences, Danderyds University Hospital, Karolinska Institutet, Stockholm.

3. Department of Medical Sciences and Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden

4. Örebro University, Faculty of Health, Department of Cardiology, Örebro, Sweden

Word count: 2733

Correspondence to: David Erlinge, Department of Cardiology, Clinical Sciences, Lund

University, Skane University Hospital, Lund; 221 85 Lund, Sweden; telephone: +46 704 872194;

fax: +46 46 157857; email: [email protected].

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Confidential: For Review OnlySummary boxes

What is already known on this topic?

In western countries, cardiac mortality and hospital admission due to myocardial infarction has

been observed to peak on Christmas and New Years’ holiday. In addition, the risk of myocardial

infarction has also been linked to football championships; hurricanes and stock market crashes. It

is therefore conjectured that factors associated with emotional stress, physical activity and

lifestyle changes may modulate the onset of myocardial infarction by acting as short-term

triggers.

What this study adds


to identify times of hazard in a large study covering 16 years of clinical MI data. We observed

higher risk of MI during Christmas/New Years and Midsummer holidays but not during Easter

holiday. The highest risk was observed during Christmas Eve and in patients over 75 years,

patients with previous diabetes and coronary artery disease.

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Confidential: For Review OnlyChristmas holidays:

In Sweden, Christmas Eve on December 24th is the main day of Christmas festivities. The

celebrations continue on Christmas day and Boxing Day.

New Year holidays:

Whereas Christmas is celebrated with the immediate family, New Year’s Eve is generally

celebrated with friends. Besides excess food and drink intake, the festivities includes awaiting

midnight to share New Year’s resolutions and wish each other a happy new year under firework

lights.

Easter Holidays:

Easter celebration is the first long weekend after winter. Families and friends meet and eat with a

focus on eggs and children dress as Easter witches.

Midsummer Holiday:

Apart from Christmas, Midsummer is the most important holiday in Sweden. On the evening

preceding the summer solstice, Midsummer Eve, Swedes gather to celebrate by dancing around a

maypole, singing, eating and drinking often in excess. It is often associated with the Christian

holiday, the Feast Day of St John the Baptist on the 24th of June.

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Confidential: For Review OnlyObjectives

To study circadian rhythm aspects, national holidays and major sport events as triggers of

myocardial infarction (MI).

Design

Retrospective observational study using the nationwide coronary care unit registry,

SWEDEHEART.

Setting

Nationwide.

Participants

A total of 283,014 cases MI were reported to the registry between 1998-2013 and included in

this study. Symptom onset date was documented for all cases and time to nearest minute for

88.20%.

Interventions

All MIs with symptom onset on Christmas/New Years, Easter, Midsummer holiday were

identified. Similarly, we identified all MIs that occurred during a FIFA world cup, UEFA

EuroCup and winter and summer Olympic games. The two weeks before and after a holiday

were set as control period and for sport events the control period was set to the same time period

1 year before and after the tournament. Circadian and circaseptan analyses were performed with

Sunday and 00.00 as reference day and hour to which all other days and hours were compared.

Incidence rate ratios were calculated using a count regression model.

Main outcome measures

Daily count of MI.

Results

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Christmas and Midsummer holidays were associated with higher risk of MI, (incidence rate ratio

(IRR)=1.15, 95% confidence interval (CI) [1.12-1.19], p<0.001) and (IRR=1.12, 95%CI [1.07-

1.18], p<0.001) respectively. The highest associated risk was observed for Christmas Eve

(IRR=1,37, 95%CI [1,29-1,46], p<0.001). No increased risk was observed during Easter holiday

or sport events. A circaseptan and circadian variation in risk of MI was observed with higher risk

during early mornings and on Mondays. Results were most pronounced in older and sicker

patients.

Conclusions



higher risk of MI particularly in older and sicker patients, suggesting a role of external triggers

in vulnerable patients.

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Confidential: For Review OnlyIntroduction

Ischemic heart disease, although declining in high income countries, remains the most common

cause of morbidity and mortality worldwide.1 Current understanding is that this disease is

multifactorial with predisposing modifiable and non-modifiable risk factors1-3. However, studies

have also shown that external factors may be involved in triggering the onset of myocardial

infarction (MI) by contributing in eliciting the rupture of unstable plaques, leading to MI. These

short-term risk factors include, but are not limited to, emotional stress, heavy physical activity

and cold weather exposure as well as air pollution3-11. Moreover, Muller et al. presented the

variation in MI incidence peaking at 9 AM and the circadian variation in MI with daily activities

increasing the risk of coronary thrombosis and MI through hemodynamic and vasoconstrictive

forces12,13. Goldberg et al. and Rocco et al. further expanded this view by adjusting for time of

waking up and both groups could show the risk of MI to be increased during the first 1-4 hours

after awakening14,15.

A number of these short-term potential triggers, ranging from earthquakes, hurricanes, wars,

sports events to stock market volatility have repeatedly been associated with a higher risk of

MI16-20. Furthermore, prior studies have shown a peak in cardiac mortality in the western world

on Christmas day, New Years’ day and during Islamic holidays in countries where this religion is

predominating21-24. Even Sir Winston Churchill was thought to have suffered from a heart attack

when visiting the White House at Christmas 194125. However, most previous studies have used

surrogate variables such as MI mortality, ambulance records, death certificates, and

administrative data including International Classification of Diseases (ICD) -codes as indicators

of MI and as such may introduce bias through misclassification and uncertainties in time of

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symptom onset. Thus, there is a lack of more granular data with exact time of symptom onset as

well as severity and type of MI in a nationwide setting.

We hypothesized that short-term risk factors may be associated with risk of MI. Furthermore; we

hypothesized that the potential risk may differ with regard to ECG subtypes of MI; ST-elevation

MI (STEMI) and non ST-elevation MI (NSTEMI). Our objective was therefore to study national

holidays, major sport events as well as circadian rhythm aspects as triggers of ECG and

biomarker positive myocardial infarctions with high-resolution data on symptom onset

documented to the nearest minute, in a large nationwide setting.

Methods

Study population

The prospective nationwide Swedish Web System for Enhancement and Development of

Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies

(SWEDEHEART) registry was used to identify cases of MI in Sweden between 1998-2013. The

SWEDEHEART registry has been described in details elsewhere; briefly, all patients with

symptoms of an acute coronary syndrome admitted to a coronary care unit or other specialized

facility in Sweden are enrolled26. The registry prospectively collects information on background

characteristics such as age, body mass index, smoking status, electrocardiographic findings as

well as other examinations, interventions, complications, laboratory measures, discharge

medications and diagnoses. The diagnosis of MI including subtypes is set based by the treating

physician’s assessment of patient at discharge. The date and time of symptom onset is

documented to the nearest minute and was used as the main variable in this study. All cases of

MI reported to the SWEDEHEART registry during the study period were included in this study.

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Study design

All cases of MI with symptom onset on Christmas/New Years, Easter, and Midsummer holiday

were identified. Christmas/New Years holidays were defined as Christmas Eve, Christmas day,

Boxing Day, New Year’s Eve, New Year’s Day and the Epiphany. Easter holiday was defined as

Good Friday, Easter Eve, Easter Day and Easter Monday. Midsummer Eve and Midsummer Day

(also known as St John’s Day) constituted Midsummer holiday. Similarly, we identified all MIs

that occurred on all Fédération Internationale de Football Association (FIFA) world cup, Union

of European Football Association (UEFA) Euro Cup and winter and summer Olympic games

during the study period. The two weeks before and after a holiday was set as control period and

for sport events the control period was set to the same time period 1 year before and after the

tournament. Circadian and circaseptan analyses were performed with Sunday and 00.00 as the

reference day and hour to which all other days and hours were compared. The primary outcome

was daily count of MI, with STEMI and NSTEMI studied independently as secondary outcome

measures. Incidence rate ratios were calculated comparing incidence rates of a period/time of

interest to a control period according to the statistical analysis section. Pre-specified subgroup

analyses were assessed for all periods of interest. These subgroups were based on sex, age ≥75

years vs. age <75 years, smoking status, diabetes, hypertension, coronary artery disease (CAD)

as well as patients on medications such as beta-blockers, calcium inhibitors, aspirin, angiotensin

converting enzyme inhibitors/angiotensin receptor blockers (ACE-I/ARB) and statins. This study

was approved by Lund University's ethical Committee (2015/297). A sensitivity analysis

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addressing the risk of MI on days involving the Swedish soccer team during FIFA world cup and

UEFA Euro Cup was conducted. In addition, sensitivity analyses adjusted for year as a

categorical variable were conducted to control for time trends in MI during the study period.

Statistical methods

Continuous variables are displayed as mean ± standard deviation. Categorical variables are

displayed as counts and percentages. Chi-square test was used to assess statistical significance

between categorical variables. Incidence rate ratios were calculated for major holidays, sport

events and day of the week as well as for hour of symptom onset by using a Poisson regression

model. Calendar week was plotted with a line graph to assess seasonality. All analyses were

conducted on complete case data and only two variables contained missing data exceeding 1%.

These were time of symptom onset and smoking status with 11.80% and 8.50% missing data

respectively. Family-wise error rate was applied within strata (total MI, NSTEMI and STEMI)

using the Hochberg method to control for type 1 errors owing to multiple testing. All statistical

analyses were performed using STATA version 14.1 for Macintosh, StataCorp, Texas, USA). A

two-sided p-value <0.05 was considered statistically significant.

Results

Patient characteristics

A total of 283,014 admissions of MI during the study period and all were included in the study.

Baseline demographics are presented in Table 1 and a total of 95,176 patients had STEMI at

admission. Patients with STEMI were on average 4 years younger, more frequently men and

current smokers compared to patients with NSTEMI.

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Major holidays

A higher risk of MI was observed for Christmas day, Boxing Day and New Years’ day but not

for New Years’ Eve and Epiphany. During Christmas/New Years holiday there was a 15%

higher risk of MI (incidence rate ratio (IRR)) =1.15 95% CI [1.12-1.19], p=<0.001). MI risk at

Christmas eve was higher than the other individual days of the holiday (IRR =1.37 95% CI

[1.29-1.46], p=<0.001) and the risk was even higher after ECG stratification of MI, risk of

NSTEMI (IRR =1.48 95%CI [1.38-1.59], p=<0.001). Easter holiday was not associated with a

higher IRR of MI while Midsummer holiday was associated with a higher risk, (IRR =1.12

95%CI [1.07-1.18], p=0.001) largely driven by NSTEMI (IRR =1.16 95%CI [1.09-1.23],

p<0.001).

Sports events

During the study period, 4 FIFA world cups and 4 European Football championships took place.

Sports events were not associated with a higher incidence of total MI, NSTEMI or STEMI,

although a trend was observed for summer Olympic games in men, but this did not reach

statistical significance after adjusting for multiple testing Table 1 and Supplementary Table 2.

Time aspects

A significant circaseptan variation in incidence of MI was observed on Mondays, also evident

after stratification into NSTEMI and STEMI, Figure 2. A clear and significantly higher incidence

of MI was observed in the analysis of hour of symptom onset, peaking at 8 AM, most prominent

for NSTEMI, Figure 2 and Supplementary Table 1.

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Subgroup and sensitivity analyses

Consistent results were observed for all subgroups with higher IRR of MI during Christmas

holiday except for the subgroup of current smokers, Supplementary Figure 1 and Supplementary

Table 2. The risk was higher in patient’s aged ≥75 years, patients with previous diabetes and

patients with previous CAD. No subgroup was particularly more affected on Easter holidays but

a statistically non-significant trend towards higher risk of MI in men during midsummer was

seen. Consistent results with higher risk of MI on Mondays were seen in all subgroups except for

current smokers Supplementary Figure 3 and Supplementary Table 2. Consistent results for hour

of symptom onset were observed in all subgroups, Supplementary Figure 4 and Supplementary

Table 2. An analysis of Christmas and Midsummer holidays was done for all patients that

underwent coronary angiography with subsequent revascularization with percutaneous coronary

intervention (PCI) or coronary artery bypass grafting (CABG) vs. patients that underwent

coronary angiography with no revascularization performed. The associated higher risk of MI

during these holidays was limited to MIs that did not undergo revascularization therapy,

Supplementary Figure 2. No associated risk was observed in the sensitivity analyses exploring

only the days when Sweden played in FIFA world cup or UEFA Euro cup. The sensitivity

analyses controlling for long-term trends in MI resulted in consistent results.

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Confidential: For Review OnlyDiscussion


using data on date and time of symptom onset, documented to the nearest minute in a large

nationwide setting with 16 years of MI data. We observed higher risk of MI during

Christmas/New Years and Midsummer holidays but not during Easter holiday. Sports events

were not associated with higher risk of MI. We observed a prominent peak incidence on

calendar week 52, Mondays and at 8 AM. This is to our knowledge the largest study utilizing

electrocardiographic and biomarker positive MI from a well-known registry. These results are

in line with studies using administrative data.

Major Holidays

We observed a remarkable 37% higher risk of MI during Christmas Eve alone compared to the

control period, by far the individual day with the highest risk of MI. Previous meta-analyses of

short-term triggers such as acute experience of anger, anxiety, sadness, grief and stress increase

MI risk, possibly explaining the higher associated risk in our study4,9. Although holiday

celebrations should be associated with the opposite, this may not be the case for all individuals.

The association of higher risk on Christmas was more pronounced in patients over 75 years,

patients with previous diabetes and patients with previous coronary artery disease highlights the

need for the medical society to raise awareness of this fragile patient group during this holiday.

These findings warrant further research to identify the mechanisms behind this phenomenon.

Understanding what factors, activities and emotions precede these MIs and how they differ from

MIs suffered on other days could result in a method to cope with this and ultimately a lesser

cardiovascular burden on society. It could be argued that relatives visiting their dear ones after a

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long time apart find them in a less than good general condition and decide to admit them to a

hospital. However, this should be followed by a decline in number of MIs the weeks after

Christmas compared to the weeks preceding Christmas. Similarly, a healthcare seeking delay

caused by patients’ unwillingness to disrupt the on-going celebration should be preceded by

lower rates of MI before Christmas as compared to after Christmas. In other words, the absence

of any decline preceding or following Christmas indicates that these behavioural aspects are not

the main contributing factors behind the Christmas peak of MI.

New Years’ eve is usually associated with the New Years’ celebrations in Sweden.

However, no associated risk was observed in our study but instead, we observed a higher risk on

New Years day, possibly explained by a negligence and masking of symptoms due to alcohol

resulting in healthcare seeking delay. The associated risk of MI during holidays was similar

between men and women except for Midsummer, which was associated with a higher risk in men

only. Men may expose themselves to risk factors like smoking, drinking and overeating to a

higher extent during this holiday and although no sex-specific statistics are available, alcohol

sale statistics from the government-owned monopoly chain of retail stores shows peaking sales

on Christmas and Midsummer27.

Time aspects

We confirm previous studies using administrative data and circadian and circaseptan variation in

MI12,14,28,29. The incidence of MI peaked on calendar week 52, on Mondays and around 8 AM.

The rate of STEMI had a normal, lightly skewed distribution whereas NSTEMI ran a more

fluctuating course over the day (Figure 2). Mondays were associated with the highest risk of MI

and differences were observed between STEMI and NSTEMI. Whereas risk of NSTEMI

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remained higher during weekdays compared to weekends, no other day of week was associated

with higher or lower risk of STEMI. However, behavioural aspect with healthcare-seeking delay

due to opening hours cannot be ruled out30. Although we used symptom onset and not admission

date, healthcare-seeking delay may still confound results, as symptom onset may be less defined

in patients with NSTEMI. The decline in incidence rate of NSTEMI on weekends and at night is

supportive of this, in contrast to STEMI, usually presenting with a more pronounced

symptomatology and minimal healthcare delay. Previous studies have shown a higher risk of MI

primarily allocated to the working population29. In contrast, we found similar patterns in retired

patients (≥75 years) as for younger patients (<75 years). Previously proposed explanation to the

circaseptan peak in MI include stressful Mondays and a rise in arterial blood pressure and heart

rate, peak cortisol and increased blood viscosity and platelet aggregability in the morning hours

may alone or in combination, explain the circadian variation.13

Sports events

Sports event periods were not associated with a higher risk of MI, which was in contrary to our

expectations with regard to previous studies17,31. Wilbert-Lampen et al. presented an increased

incidence in MI in Greater München area during FIFA world cup in Germany 2006. A number of

aspects may contribute to the discrepancy in results. First of all, the fact that Germany was the

host of the tournament might infer involvement in the sport even by non-dedicated fans. In

addition, the associated risk was restricted to days involving the German soccer team and highest

during the day of the quarter and semi-finals. There was a complete lack of risk on the day the

German team played for third place and, the only day that was associated with a higher risk and

not involving the German team was the final. Altogether, these factors indicate that a stronger

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emotional stress may be required to trigger MI. We tried to address this in our sensitivity

analysis of days involving the Swedish team playing which did not show any associated risk.

Moreover, no subgroup suffered a higher risk of MI during any sport periods that were studied

thus normal watching sport events can be considered safe.

Pathophysiological aspects

We were able to characterize MI to a higher degree than previously and this allowed us to study

STEMI and NSTEMI independently together with a wide range of subgroups. Our results

showed consistently higher risk of MI due to higher rates of NSTEMI, elderly patients and

patients with previous diabetes, hypertension, coronary artery disease and those on previous

medications with regard to all studied potential triggers, highlighting the concept of vulnerable

patients. Whereas the current understanding of vulnerable plaques is that it is a local process of a

systemic disease (atherosclerosis), the concept of the vulnerable patients is broader, involving

blood vulnerable to thrombosis and myocardium vulnerable to arrhythmias among other risk

factors32. It cannot be ruled out that activities and emotions associated with holiday’s results in

myocardial infarction secondary to ischemia due to an increased oxygen demand in elder and

sicker patients. This is supported by the subgroup analysis on Christmas and New Years’ holiday

(Supplementary Figure 2) that showed an incremental risk increase of MI with each age quartile

in addition to the lack of risk of STEMI, as type 2 infarctions generally do not present as

STEMI33. However, infarct type classification was not introduced in the SWEDEHEART

registry until 2010 and in order to address this topic; we conducted a post hoc analysis of risk of

MI resulting in a coronary angiography between 2004-2013. Neither Christmas nor Midsummer

holiday were associated with risk of an MI resulting in revascularization; these holidays were

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rather associated with MI in which PCI or surgery was not deemed necessary. This suggests that

a large proportion of MI with non-occlusive coronary arteries may account for the higher risk of

MI during these holidays. Although this post hoc analysis did not take into account chronic total

occlusions or distal occlusions that were left untreated by the interventionist, these findings

warrant further investigation.

The rationale behind our subgroup analyses i.e. patients on previous medications was to

investigate possible inhibitory mechanisms of certain pharmacotherapies on the mechanisms of

the short term triggers of MI. Medications lowering heart rate, reducing blood pressure, lipids

and platelet aggregation might reduce plaque vulnerability to external triggers. For example,

beta-adrenergic inhibitors have been shown to blunt the circadian variation in MI by reducing

heart rate and blood pressure and increase coronary blood flow by prolonging diastole.34

However, in our study, patients on cardiovascular medications had similar or higher risk of MI

during holidays, our explanation to this is thus in line with our main theory - the medications

are surrogate measures of a sicker population, more vulnerable to external triggers. On the

contrary, the subgroup analyses of circadian variation were rather associated with lower risk,

Supplementary figure 4, in line with previous studies suggesting that these medications partially

blunting the mechanisms of short-term triggers of MI.

Limitations

Due to the nature of this study as an observational study, causality cannot be determined, as

unobserved confounders cannot be ruled out. Previous publications have shown a higher

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incidence of MI during colder temperatures. However, it is unlikely that national holidays should

be associated with lower temperature to bias the results since control periods two weeks before

and after holidays were used.

Conclusion



higher risk of MI. Consistently, we observed a higher risk in older and sicker patients,

suggesting a role of external triggers in the vulnerable patients.

Conflicts of interest

None of the authors have anything to disclose.

Funding

This work was supported by The Swedish Heart and Lung Foundation, Swedish Scientific

Research Council, SSF (TOTAL-AMI), Knut and Alice Wallenberg Foundation, ALF and Skane

University Hospital funds.

Acknowledgment

The authors would like to thank the staff members at all coronary care units in Sweden for their

help and cooperation in contributing data to the Swedish Web-system for Enhancement and

Development of Evidence-based care in Heart disease Evaluated According to Recommended

Therapies (SWEDEHEART) system. The sponsors had no involvement in the study design,

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collection, analysis or interpretation of data or writing of the manuscript or in the decision to

submit manuscript for publication.

Transparency Statement

M.A.Mohammad affirms that this manuscript is an honest, accurate, and transparent account of

the study being reported; that no important aspects of the study have been omitted; and that any

discrepancies from the study as planned (and, if relevant, registered) have been explained.

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Table 1. Baseline demographics. Total MI STEMI NSTEMI

283014 95176 187838

Age (years) 71.7 ± 12.2 69.1 ± 12.5 73.0 ± 11.8

Table 1. Baseline demographics. Total MI STEMI NSTEMI

n=283014 n=95176 n=187838

Age (years) 71.7 ± 12.2 69.1 ± 12.5 73.0 ± 11.8

Men 180205 (63.7%) 63119 (66.3%) 117086 (62.3%)

Women 102809 (36.3%) 32057 (33.7%) 70752 (37.7%)

BMI 26.7 ± 5.9 26.6 ± 7.1 26.8 ± 5.2

E-GFR 68.2 ± 24.1 73,4 ± 23.1 65.8 ± 24.2

Current Smoker 55673 (21.5%) 24531 (27.9%) 31142 (18.2%)

Medical history

Diabetes 61955 (21.9%) 15806 (16.6%) 46149 (24.6%)

Hypertension 123436 (43.6%) 36306 (38.1%) 87130 (46.4%)


MI 91283 (32.3%) 19345 (20.3%) 71938 (38.3%)

PCI 32846 (11.6%) 7574 (8.0%) 25272 (13.5%)

CABG 23971 (8.5%) 3711 (3.9%) 20260 (10.8%)


Stroke 17116 (6.0%) 3935 (4.1%) 13181 (7.0%)


Beta-blockers 120904 (42.7%) 29851 (31.4%) 91053 (48.5%)


Aspirin 123647 (43.7%) 29258 (30.7%) 94389 (50.3%)

ACE-I/ARB 88592 (31.3%) 20955 (22.0%) 67637 (36.0%)

Statins 75381 (26.6%) 16978 (17.8%) 58403 (31.1%)

Diuretics 87367 (30.9%) 19180 (20.2%) 68187 (36.3%)

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Men 180205 (63.67%) 63119 (66.32%) 117086 (62.33%)

Women 102809 (36.33%) 32057 (33.68%) 70752 (37.67%)

BMI 26.7 ± 5.9 26.6 ± 7.1 26.8 ± 5.2

E-GFR 68.2 ± 24.1 73,4 ± 23.1 65.8 ± 24.2

Current Smoker 55673 (19.67%) 24531 (25.77%) 31142 (16.58%)

Medical history

Diabetes 61955 (21.89%) 15806 (16.61%) 46149 (24.57%)

Hypertension 123436 (43.61%) 36306 (38.15%) 87130 (46.39%)


MI 91283 (32.25%) 19345 (20.33%) 71938 (38.30%)

PCI 32846 (11.61%) 7574 (7.96%) 25272 (13.45%)

CABG 23971 (8.47%) 3711 (3.90%) 20260 (10.79)


Stroke 17116 (6.05%) 3935 (4.13%) 13181 (7.02%)


Beta-blockers 120904 (42.72%) 29851 (31.36%) 91053 (48.47%)


Aspirin 123647 (43.69%) 29258 (30.74%) 94389 (50.25%)

ACE-I/ARB 88592 (31.30%) 20955 (22.02%) 67637 (36.01%)

Statins 75381 (26.64%) 16978 (17.84%) 58403 (31.09%)

Diuretics 87367 (30.87%) 19180 (20.15%) 68187 (36.30%)

Table 1. Baseline demographics for the study population

ACE-I/ARB= Angiotensin converting enzyme inhibitor/angiotensin receptor blocker; BMI=Body Mass Index;

CABG=coronary artery bypass graft; E-GFR=estimated glomerular filtration rate; MI=myocardial infarction;

NSTEMI= non ST-Elevation MI; PCI= percutaneous coronary

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Confidential: For Review OnlyTable 2. Results.

FIFA= Fédération Internationale de Football Association. All P-values are adjusted for multiple testing.

*=p<0.05

Table 2. Results. Total MI Non ST-Elevation MI ST-Elevation MIPeriod of Interest

ControlPeriod

Period of Interest

ControlPeriod

Period of Interest

ControlPeriod

Holidays IR/day IR/day IRR (95%CI) IR/day IR/day IRR (95%CI) IR/day IR/day IRR (95%CI)Christmas/New Year 57.9 50.3 1.15 (1.12-1.19)*** 40.1 33 1.22 (1.17-1.26)*** 17.8 17.3 1.03 (0.98-1.09)Christmas Eve 69.1 50.3 1.37 (1.29-1.46)*** 48.9 33 1.48 (1.38-1.59)*** 20.2 17.3 1.17 (1.05-1.31)Christmas Day 64.9 50.3 1.29 (1.21-1.38)*** 46.6 33 1.41 (1.31-1.52)*** 18.3 17.3 1.06 (0.95-1.19)Boxing Day 61.1 50.3 1.21 (1.14-1.3)*** 41.2 33 1.25 (1.15-1.35)*** 19.9 17.3 1.15 (1.03-1.29)New Years Eve 46.3 50.3 0.92 (0.86-0.99) 31.1 33 0.94 (0.86-1.03) 15.2 17.3 0.88 (0.78-1)New Years Day 60.4 50.3 1.2 (1.12-1.28)*** 43.1 33 1.3 (1.21-1.41)*** 17.3 17.3 1 (0.89-1.13)Epiphany 46 50.3 0.92 (0.85-0.99) 29.9 33 0.91 (0.83-0.99) 16.1 17.3 0.93 (0.82-1.06)Easter Holidays 52.5 50.3 1.04 (1.01-1.08) 35 33.6 1.04 (1-1.09) 17.5 16.7 1.05 (0.99-1.12)Good Friday 50.9 50.3 1.01 (0.94-1.09) 32.1 33.6 0.96 (0.88-1.04) 18.8 16.7 1.13 (1.01-1.27)Easter Eve 51.9 50.3 1.03 (0.96-1.11) 35.3 33.6 1.05 (0.97-1.14) 16.6 16.7 1 (0.88-1.13)Easter Day 55.1 50.3 1.1 (1.03-1.17) 37.1 33.6 1.11 (1.02-1.2) 18 16.7 1.08 (0.96-1.21)Easter Monday 52.2 50.3 1.04 (0.97-1.11) 35.6 33.6 1.06 (0.97-1.15) 16.6 16.7 0.99 (0.88-1.12)Midsummer holidays 51.9 46.2 1.12 (1.07-1.18)** 35.3 30.4 1.16 (1.09-1.23)** 16.6 15.8 1.05 (0.96-1.15)Sport periods UEFA Euro Cup 47.3 46.9 1.01 (0.97-1.04) 31 31.1 1 (0.95-1.04) 16.3 15.8 1.03 (0.97-1.09)FIFA World Cup 45.2 46.2 0.98 (0.95-1.01) 29.8 30.7 0.97 (0.93-1.01) 15.4 15.5 0.99 (0.94-1.05)Winter Olympic Games 48.2 50 0.96 (0.92-1.01) 31.6 32.7 0.97 (0.92-1.02) 16.6 17.3 0.96 (0.89-1.03)Summer Olympic Games 47.4 45.6 1.04 (1-1.08) 31.6 30.4 1.04 (0.99-1.1) 15.8 15.2 1.04 (0.96-1.12)

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24

*p<0.01

*p<0.001

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Confidential: For Review OnlyFigure 1. Results of national holidays and week of symptom onset.

Shown are the associated risks of all MI, ST-elevation MI and Non ST-Elevation MI expressed

as incidence rate ratios for all major national holidays. Christmas/New Years include Christmas

Eve, Christmas Day, Boxing Day, New Years Eve and day as well as the Epiphany. Easter

holiday includes Good Friday, Easter Eve and Day and Easter Monday. P-values after

adjustment for multiple testing are presented in Table 2. Lower figure visualize the total number

of infarctions by calendar week, peaking on calendar week 52.

Figure 2. Results of day of week and hour of symptom onset.

Shown are the associated risks of overall MI, ST-elevation MI and Non ST-Elevation MI and

days of the week and hour of symptom onset expressed as incidence rate ratios. Reference period

for day of week is Sunday and reference hour for hour of symptom onset is 00:00. Hours are

defined as the hour of symptom onset, i.e. 00:00 - 00:59. P-values after adjustment for multiple

testing are presented in Supplementary Table 1.

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Confidential: For Review OnlySUPPLEMENTARY FIGURES


Shown are the associated risks overall MI in various subgroups and major national holidays

expressed as incidence rate ratios. Christmas/New years include Christmas Eve, Christmas Day,

Boxing Day, New Years Eve and Day as well as the epiphany. Easter holiday includes Good

Friday, Easter Eve and Day and Easter Monday. P-value<0.05 for all bars not crossing the red

line. P-values after adjustment for multiple testing are presented in Supplementary Table 1.


Left figure shows the associated risk of holidays on MI requiring revascularization after coronary

angiography was performed vs. those who did not undergo PCI/CABG. Right figure shows the

associated risk of MI on Christmas/New Years’ holiday for each age quartile. Christmas/New

Years’ include Christmas Eve, Christmas Day, Boxing Day, New Years’ Eve and Day as well as

the epiphany. P-value<0.05 for all bars not crossing the red line.

Suppementary Figure 3. Subgroup analyses of day of week.

Shown are the associated risks overall MI in various subgroups and day of week expressed as

incidence rate ratio. Reference period for day of week is Sunday and reference hour for hour of

symptom onset is 00:00. P-values after adjustment for multiple testing are presented in

Supplementary Table 1.

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27

Suppementary Figure 4. Subgroup analyses of hour of symptom onset

Shown are the associated risks overall MI in various subgroups and hour of symptom onset

expressed as incidence rate ratios. Reference period is 00:00. P-values after adjustment for


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Figure 1. Results of national holidays and calendar week.Shown are the associated risks of all MI, ST-elevation MI and Non ST-Elevation MI expressed as incidence

rate ratios for all major national holidays. Christmas/New Years include Christmas Eve, Christmas Day, Boxing Day, New Years Eve and day as well as the Epiphany. Easter holiday includes Good Friday, Easter Eve and Day and Easter Monday. P-values after adjustment for multiple testing are presented in Table 2.

Lower figure visualize the total number of infarctions by calendar week, peaking on calendar week 52.

150x179mm (300 x 300 DPI)

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Figure 2. Results of day of week and hour of symptom onset.Shown are the associated risks of overall MI, ST-elevation MI and Non ST-Elevation MI expressed as

incidence rate ratios for days of the week and hours of the day. The reference period for day of week is Sunday and reference hour for hour of symptom onset is 00:00. Hours are defined as the hour of symptom onset, i.e. 00:00 - 00:59. P-values after adjustment for multiple testing are presented in Supplementary

Table 1.

150x179mm (300 x 300 DPI)

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Confidential: For Review OnlySupplementary Materials

Supplementary Table 1. Sunday IRR (95%CI) Q-value IRR (95%CI) Q-value IRR (95%CI) Q-valueMonday 1,09 (1,08-1,11) <0,001 1,12 (1,1-1,13) <0,001 1,05 (1,03-1,08) 0,024Tuesday 1,02 (1,01-1,03) 1 1,03 (1,02-1,05) 0,07 0,99 (0,97-1,02) 0,993Wednesday 1,02 (1,01-1,04) 0,327 1,04 (1,02-1,06) 0,002 0,99 (0,97-1,01) 0,993Thursday 1,03 (1,02-1,04) 0,019 1,05 (1,03-1,07) <0,001 0,99 (0,97-1,02) 0,993Friday 1,02 (1,01-1,03) 1 1,03 (1,02-1,05) 0,002 0,99 (0,97-1,02) 0,993Saturday 0,98 (0,96-0,99) 0,389 0,97 (0,96-0,99) 0,736 0,98 (0,96-1,01) 0,993Hour of symptom onset

01:00 0,89 (0,86-0,91) <0,001 0,88 (0,85-0,91) <0,001 0,98 (0,93-1,04) 0,99302:00 0,92 (0,89-0,94) <0,001 0,9 (0,87-0,93) <0,001 1,01 (0,96-1,07) 0,99303:00 0,91 (0,88-0,94) <0,001 0,89 (0,86-0,92) <0,001 1,02 (0,96-1,07) 0,99304:00 0,86 (0,84-0,89) <0,001 0,85 (0,83-0,88) <0,001 0,99 (0,94-1,05) 0,99305:00 0,83 (0,8-0,85) <0,001 0,81 (0,78-0,84) <0,001 0,99 (0,94-1,04) 0,99306:00 0,95 (0,92-0,97) 0,042 0,9 (0,87-0,93) <0,001 1,04 (0,99-1,09) 0,99307:00 1,09 (1,07-1,12) <0,001 1,01 (0,98-1,05) 0,998 1,11 (1,05-1,16) 0,02308:00 1,58 (1,55-1,62) <0,001 1,42 (1,38-1,46) <0,001 1,28 (1,22-1,34) <0,00109:00 1,17 (1,14-1,2) <0,001 1,04 (1,01-1,07) 0,998 1,18 (1,13-1,24) <0,00110:00 1,24 (1,21-1,27) <0,001 1,08 (1,04-1,11) 0,001 1,23 (1,17-1,28) <0,00111:00 1 (0,97-1,02) 1 0,89 (0,86-0,92) <0,001 1,15 (1,1-1,2) <0,00112:00 1,23 (1,2-1,26) <0,001 1,11 (1,08-1,15) <0,001 1,18 (1,13-1,24) <0,00113:00 0,91 (0,89-0,94) <0,001 0,85 (0,82-0,88) <0,001 1,06 (1,01-1,12) 0,99314:00 0,96 (0,93-0,99) 1 0,89 (0,86-0,92) <0,001 1,08 (1,03-1,13) 0,99315:00 1 (0,97-1,03) 1 0,94 (0,91-0,97) 0,042 1,08 (1,03-1,14) 0,74516:00 0,9 (0,88-0,93) <0,001 0,87 (0,84-0,9) <0,001 1,05 (1-1,1) 0,99317:00 0,85 (0,82-0,87) <0,001 0,83 (0,8-0,86) <0,001 1 (0,95-1,05) 0,99318:00 0,89 (0,86-0,91) <0,001 0,87 (0,84-0,9) <0,001 1,02 (0,97-1,07) 0,99319:00 0,86 (0,83-0,88) <0,001 0,84 (0,81-0,87) <0,001 1 (0,95-1,05) 0,99320:00 0,98 (0,95-1) 1 0,96 (0,93-0,99) 0,998 1,01 (0,96-1,07) 0,99321:00 0,89 (0,86-0,91) <0,001 0,88 (0,85-0,91) <0,001 0,99 (0,94-1,04) 0,99322:00 0,95 (0,92-0,97) 0,036 0,93 (0,9-0,96) 0,004 1,01 (0,96-1,06) 0,99323:00 0,93 (0,91-0,96) 0,001 0,92 (0,89-0,95) <0,001 1,01 (0,96-1,07) 0,993

Supplementary Table 1. Results of circadian and circaseptan variation.All P-values are adjusted for multiple testing. Hours are defined as the hour of symptom onset, i.e. 00:00 - 00:59. Sunday and midnight were set as reference periods.

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Confidential: For Review OnlySupplementary Table 2.

Total MI Non ST-Elevation MI ST-Elevation MI

Christmas/New Years IRR (95%CI) Q-value IRR (95%CI) Q-value IRR (95%CI) Q-value

Men 1,15 (1,11-1,19) <0,001 1,22 (1,16-1,27) <0,001 1,02 (0,96-1,09) 0,993Women 1,16 (1,11-1,22) <0,001 1,21 (1,14-1,29) <0,001 1,06 (0,97-1,16) 0,993Age≥75yo 1,22 (1,17-1,27) <0,001 1,28 (1,21-1,34) <0,001 1,06 (0,98-1,16) 0,993Age<75yo 1,1 (1,05-1,14) 0,009 1,15 (1,09-1,21) <0,001 1,01 (0,95-1,09) 0,993Current Smoker 1,09 (1,02-1,17) 1,000 1,13 (1,03-1,24) 0,998 1,05 (0,94-1,16) 0,993Non Smoker 1,16 (1,12-1,2) <0,001 1,18 (1,13-1,22) <0,001 1,12 (1,08-1,17) <0,001Diabetes 1,28 (1,2-1,36) <0,001 1,33 (1,24-1,42) <0,001 1,12 (0,99-1,27) 0,993No Diabetes 1,11 (1,08-1,15) <0,001 1,18 (1,13-1,23) <0,001 1,01 (0,95-1,07) 0,993Hypertension 1,16 (1,11-1,22) <0,001 1,21 (1,15-1,28) <0,001 1,05 (0,96-1,14) 0,993No Hypertension 1,13 (1,09-1,18) <0,001 1,21 (1,15-1,27) <0,001 1,01 (0,95-1,09) 0,993CAD 1,26 (1,2-1,32) <0,001 1,26 (1,2-1,32) <0,001 1,26 (1,2-1,32) <0,001No CAD 1,09 (1,05-1,14) 0,002 1,15 (1,1-1,21) <0,001 1 (0,94-1,07) 0,993Beta-blockers 1,21 (1,16-1,27) <0,001 1,27 (1,21-1,33) <0,001 1,06 (0,96-1,16) 0,993No Beta-blockers 1,1 (1,06-1,15) 0,001 1,16 (1,1-1,22) <0,001 1,02 (0,96-1,09) 0,993Ca-inhibitors 1,24 (1,16-1,33) <0,001 1,3 (1,2-1,41) <0,001 1,07 (0,93-1,23) 0,993No Ca-inhibitors 1,13 (1,1-1,17) <0,001 1,19 (1,14-1,24) <0,001 1,03 (0,97-1,09) 0,993Aspirin 1,22 (1,16-1,27) <0,001 1,26 (1,2-1,33) <0,001 1,07 (0,98-1,18) 0,993No Aspirin 1,1 (1,06-1,15) 0,002 1,17 (1,11-1,23) <0,001 1,01 (0,95-1,08) 0,993ACE-I/ARB 1,15 (1,09-1,21) <0,001 1,16 (1,1-1,22) <0,001 1,19 (1,12-1,26) <0,001No ACE-I/ARB 1,16 (1,12-1,2) <0,001 1,22 (1,15-1,29) <0,001 0,91 (0,84-0,99) 0,993Statins 1,19 (1,12-1,25) <0,001 1,26 (1,18-1,34) <0,001 0,95 (0,84-1,08) 0,993No Statins 1,14 (1,1-1,18) <0,001 1,19 (1,14-1,25) <0,001 1,05 (0,99-1,12) 0,993

Easter

Men 1,04 (1-1,09) 1,000 1,04 (0,98-1,1) 0,998 1,05 (0,97-1,13) 0,993Women 1,05 (0,99-1,11) 1,000 1,05 (0,98-1,13) 0,998 1,05 (0,94-1,17) 0,993Age≥75yo 1,07 (1,02-1,13) 1,000 1,08 (1,02-1,15) 0,998 1,05 (0,95-1,17) 0,993Age<75yo 1,02 (0,97-1,07) 1,000 1 (0,94-1,07) 0,998 1,05 (0,97-1,13) 0,993Current Smoker 0,99 (0,91-1,07) 1,000 0,97 (0,87-1,09) 0,998 1,01 (0,89-1,14) 0,993Non Smoker 1,07 (1,03-1,12) 0,422 1,07 (1,02-1,12) 0,998 1,07 (1,01-1,12) 0,993Diabetes 1,11 (1,03-1,2) 1,000 1,15 (1,06-1,26) 0,490 0,99 (0,84-1,16) 0,993No Diabetes 1,03 (0,99-1,07) 1,000 1,01 (0,96-1,06) 0,998 1,06 (0,99-1,14) 0,993Hypertension 1,08 (1,02-1,14) 1,000 1,08 (1,01-1,15) 0,998 1,09 (0,98-1,2) 0,993No Hypertension 1,02 (0,97-1,07) 1,000 1,02 (0,96-1,09) 0,998 1,03 (0,95-1,11) 0,993CAD 1,11 (1,04-1,18) 0,327 1,11 (1,04-1,18) 0,296 1,11 (1,04-1,18) 0,889No CAD 1,01 (0,97-1,06) 1,000 0,99 (0,93-1,05) 0,998 1,03 (0,96-1,11) 0,993Beta-blockers 1,08 (1,02-1,14) 1,000 1,09 (1,02-1,16) 0,998 1,06 (0,95-1,19) 0,993No Beta-blockers 1,02 (0,97-1,07) 1,000 1 (0,94-1,07) 0,998 1,04 (0,97-1,13) 0,993Ca-inhibitors 1,13 (1,04-1,23) 1,000 1,11 (1,01-1,23) 0,998 1,19 (1,01-1,4) 0,993No Ca-inhibitors 1,03 (0,99-1,07) 1,000 1,03 (0,98-1,08) 0,998 1,03 (0,96-1,1) 0,993Aspirin 1,07 (1,01-1,13) 1,000 1,06 (1-1,13) 0,998 1,07 (0,96-1,2) 0,993No Aspirin 1,03 (0,98-1,08) 1,000 1,02 (0,96-1,09) 0,998 1,04 (0,96-1,12) 0,993ACE-I/ARB 1,1 (1,03-1,17) 1,000 1,1 (1,03-1,17) 0,998 1,11 (1,03-1,19) 0,993

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Confidential: For Review OnlyNo ACE-I/ARB 1,02 (0,98-1,07) 1,000 1,04 (0,97-1,12) 0,998 1,04 (0,95-1,15) 0,993Statins 1,04 (0,97-1,12) 1,000 1,07 (0,98-1,15) 0,998 0,95 (0,81-1,11) 0,993No Statins 1,05 (1-1,09) 1,000 1,03 (0,98-1,09) 0,998 1,07 (1-1,15) 0,993

Midsummer

Men 1,15 (1,08-1,23) 0,003 1,21 (1,12-1,3) 0,001 1,06 (0,95-1,18) 0,993Women 1,07 (0,98-1,16) 1,000 1,09 (0,98-1,2) 0,998 1,03 (0,89-1,2) 0,993Age≥75yo 1,14 (1,06-1,22) 0,246 1,18 (1,08-1,29) 0,049 1,02 (0,88-1,18) 0,993Age<75yo 1,11 (1,04-1,19) 0,726 1,14 (1,05-1,25) 0,814 1,07 (0,95-1,19) 0,993Current Smoker 1,03 (0,91-1,15) 1,000 1,11 (0,95-1,29) 0,998 0,93 (0,77-1,11) 0,993Non Smoker 1,14 (1,08-1,21) 0,005 1,16 (1,09-1,24) 0,001 1,11 (1,04-1,19) 0,993Diabetes 1,19 (1,07-1,32) 0,454 1,22 (1,09-1,38) 0,330 1,08 (0,87-1,34) 0,993No Diabetes 1,11 (1,05-1,17) 0,196 1,14 (1,07-1,23) 0,078 1,04 (0,95-1,15) 0,993Hypertension 1,18 (1,1-1,28) 0,004 1,23 (1,12-1,34) 0,003 1,09 (0,95-1,25) 0,993No Hypertension 1,08 (1,01-1,16) 1,000 1,11 (1,02-1,21) 0,998 1,03 (0,92-1,15) 0,993CAD 1,19 (1,1-1,29) 0,010 1,19 (1,09-1,29) 0,018 1,19 (1,1-1,29) 0,028No CAD 1,09 (1,02-1,16) 1,000 1,13 (1,04-1,23) 0,998 1,02 (0,92-1,13) 0,993Beta-blockers 1,21 (1,12-1,3) <0,001 1,27 (1,17-1,38) <0,001 1,03 (0,88-1,21) 0,993No Beta-blockers 1,06 (0,99-1,14) 1,000 1,06 (0,98-1,16) 0,998 1,06 (0,95-1,18) 0,993Ca-inhibitors 1,18 (1,05-1,32) 1,000 1,29 (1,13-1,47) 0,065 0,89 (0,7-1,15) 0,993No Ca-inhibitors 1,11 (1,05-1,18) 0,070 1,13 (1,06-1,21) 0,144 1,08 (0,98-1,18) 0,993Aspirin 1,23 (1,14-1,32) <0,001 1,28 (1,18-1,39) <0,001 1,07 (0,91-1,25) 0,993No Aspirin 1,04 (0,97-1,12) 1,000 1,04 (0,95-1,14) 0,998 1,04 (0,94-1,16) 0,993ACE-I/ARB 1,15 (1,06-1,26) 0,515 1,17 (1,07-1,28) 0,288 1,15 (1,04-1,27) 0,993No ACE-I/ARB 1,11 (1,04-1,18) 0,277 1,14 (1,04-1,26) 0,998 1,06 (0,93-1,21) 0,993Statins 1,23 (1,12-1,35) 0,009 1,24 (1,12-1,38) 0,022 1,17 (0,95-1,42) 0,993No Statins 1,09 (1,02-1,15) 1,000 1,13 (1,04-1,21) 0,590 1,03 (0,93-1,13) 0,993

UEFA Euro Cup

Men 0,99 (0,95-1,04) 1,000 0,97 (0,92-1,03) 0,998 1,04 (0,96-1,12) 0,993Women 1,03 (0,97-1,09) 1,000 1,04 (0,97-1,12) 0,998 1,01 (0,91-1,13) 0,993Age≥75yo 1,01 (0,96-1,06) 1,000 1,01 (0,95-1,08) 0,998 1 (0,91-1,11) 0,993Age<75yo 1,01 (0,96-1,06) 1,000 0,98 (0,92-1,05) 0,998 1,05 (0,97-1,13) 0,993Current Smoker 1,03 (0,95-1,11) 1,000 1,03 (0,92-1,14) 0,998 1,03 (0,91-1,16) 0,993Non Smoker 0,99 (0,95-1,04) 1,000 0,98 (0,94-1,03) 0,998 1,01 (0,96-1,06) 0,993Diabetes 1 (0,93-1,08) 1,000 0,95 (0,87-1,04) 0,998 1,15 (1-1,34) 0,993No Diabetes 1,01 (0,97-1,05) 1,000 1,01 (0,96-1,07) 0,998 1,01 (0,94-1,08) 0,993Hypertension 1,01 (0,95-1,06) 1,000 0,98 (0,92-1,04) 0,998 1,08 (0,98-1,19) 0,993No Hypertension 1,01 (0,96-1,06) 1,000 1,02 (0,96-1,08) 0,998 1 (0,92-1,09) 0,993CAD 1,02 (0,96-1,08) 1,000 1,02 (0,96-1,08) 0,998 1,01 (0,95-1,07) 0,993No CAD 1 (0,96-1,05) 1,000 0,99 (0,93-1,05) 0,998 1,02 (0,95-1,09) 0,993Beta-blockers 1,01 (0,96-1,07) 1,000 0,98 (0,92-1,05) 0,998 1,09 (0,98-1,22) 0,993No Beta-blockers 1 (0,96-1,05) 1,000 1,01 (0,95-1,07) 0,998 1 (0,93-1,08) 0,993Ca-inhibitors 0,99 (0,91-1,08) 1,000 0,99 (0,89-1,09) 0,998 0,99 (0,84-1,16) 0,993No Ca-inhibitors 1,01 (0,97-1,05) 1,000 1 (0,95-1,05) 0,998 1,04 (0,97-1,11) 0,993Aspirin 1 (0,95-1,06) 1,000 1 (0,94-1,06) 0,998 1,01 (0,91-1,13) 0,993

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Confidential: For Review OnlyNo Aspirin 1,01 (0,97-1,06) 1,000 1 (0,93-1,06) 0,998 1,04 (0,96-1,12) 0,993ACE-I/ARB 0,99 (0,93-1,06) 1,000 0,98 (0,92-1,05) 0,998 0,99 (0,93-1,07) 0,993No ACE-I/ARB 1,02 (0,97-1,06) 1,000 1,19 (1,11-1,27) <0,001 1,26 (1,16-1,38) <0,001Statins 1 (0,93-1,07) 1,000 0,98 (0,91-1,06) 0,998 1,07 (0,93-1,24) 0,993No Statins 1,01 (0,97-1,05) 1,000 1 (0,95-1,06) 0,998 1,02 (0,95-1,09) 0,993

FIFA world cup

Men 0,99 (0,95-1,03) 1,000 0,98 (0,93-1,03) 0,998 1,01 (0,94-1,08) 0,993Women 0,96 (0,91-1,01) 1,000 0,96 (0,9-1,02) 0,998 0,96 (0,87-1,06) 0,993Age≥75yo 0,95 (0,91-1) 1,000 0,95 (0,9-1,01) 0,998 0,96 (0,88-1,05) 0,993Age<75yo 1 (0,95-1,04) 1,000 0,99 (0,94-1,05) 0,998 1,01 (0,94-1,08) 0,993Current Smoker 0,93 (0,86-1) 1,000 0,94 (0,85-1,03) 0,998 0,92 (0,83-1,03) 0,993Non Smoker 1 (0,96-1,03) 1,000 1 (0,96-1,04) 0,998 1,03 (0,98-1,08) 0,993Diabetes 0,96 (0,9-1,03) 1,000 0,95 (0,87-1,03) 0,998 1,01 (0,88-1,16) 0,993No Diabetes 0,98 (0,94-1,02) 1,000 0,98 (0,93-1,02) 0,998 0,99 (0,93-1,05) 0,993Hypertension 0,94 (0,9-0,99) 1,000 0,93 (0,88-0,99) 0,998 0,96 (0,88-1,06) 0,993No Hypertension 1,01 (0,96-1,05) 1,000 1 (0,95-1,06) 0,998 1,01 (0,94-1,09) 0,993CAD 0,99 (0,94-1,05) 1,000 1 (0,95-1,05) 0,998 0,99 (0,94-1,05) 0,993No CAD 0,97 (0,93-1,01) 1,000 0,96 (0,91-1,01) 0,998 0,96 (0,9-1,03) 0,993Beta-blockers 0,95 (0,9-1) 1,000 0,94 (0,89-1) 0,998 0,97 (0,87-1,07) 0,993No Beta-blockers 1 (0,96-1,04) 1,000 1 (0,94-1,05) 0,998 1 (0,94-1,07) 0,993Ca-inhibitors 1,01 (0,93-1,09) 1,000 1,01 (0,92-1,11) 0,998 0,99 (0,86-1,15) 0,993No Ca-inhibitors 0,97 (0,94-1,01) 1,000 0,96 (0,92-1,01) 0,998 0,99 (0,93-1,05) 0,993Aspirin 0,95 (0,9-1) 1,000 0,95 (0,9-1) 0,998 0,95 (0,86-1,05) 0,993No Aspirin 1 (0,96-1,05) 1,000 1 (0,94-1,05) 0,998 1,01 (0,94-1,08) 0,993ACE-I/ARB 0,91 (0,85-0,96) 0,486 0,91 (0,86-0,97) 0,910 0,92 (0,86-0,99) 0,993No ACE-I/ARB 1,01 (0,97-1,05) 1,000 0,88 (0,82-0,94) 0,093 0,89 (0,81-0,97) 0,993Statins 0,9 (0,85-0,97) 0,884 0,9 (0,84-0,97) 0,998 0,92 (0,81-1,06) 0,993No Statins 1 (0,97-1,04) 1,000 1 (0,96-1,05) 0,998 1 (0,95-1,07) 0,993

Winter Olympic Games

Men 0,99 (0,94-1,04) 1,000 1 (0,94-1,07) 0,998 0,96 (0,88-1,05) 0,993Women 0,92 (0,86-0,99) 1,000 0,91 (0,83-0,99) 0,998 0,94 (0,83-1,07) 0,993Age≥75yo 0,98 (0,92-1,04) 1,000 0,96 (0,89-1,04) 0,998 1,01 (0,9-1,14) 0,993Age<75yo 0,95 (0,9-1,01) 1,000 0,97 (0,9-1,05) 0,998 0,92 (0,84-1,01) 0,993Current Smoker 0,95 (0,86-1,05) 1,000 1,04 (0,91-1,18) 0,998 0,85 (0,73-0,98) 0,993Non Smoker 0,97 (0,92-1,02) 1,000 0,97 (0,92-1,03) 0,998 0,97 (0,91-1,03) 0,993Diabetes 0,9 (0,82-0,98) 1,000 0,92 (0,83-1,03) 0,998 0,82 (0,69-0,99) 0,993No Diabetes 0,98 (0,93-1,03) 1,000 0,98 (0,92-1,04) 0,998 0,98 (0,91-1,06) 0,993Hypertension 0,91 (0,86-0,98) 1,000 0,89 (0,82-0,96) 0,998 0,97 (0,86-1,09) 0,993No Hypertension 1 (0,94-1,06) 1,000 1,03 (0,96-1,11) 0,998 0,95 (0,86-1,04) 0,993CAD 1,01 (0,94-1,09) 1,000 1,02 (0,95-1,09) 0,998 1,02 (0,95-1,1) 0,993No CAD 0,93 (0,89-0,99) 1,000 0,94 (0,87-1,01) 0,998 0,94 (0,86-1,02) 0,993

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Confidential: For Review OnlyBeta-blockers 0,96 (0,9-1,03) 1,000 0,96 (0,89-1,04) 0,998 0,96 (0,85-1,1) 0,993No Beta-blockers 0,96 (0,91-1,02) 1,000 0,97 (0,9-1,05) 0,998 0,95 (0,87-1,04) 0,993Ca-inhibitors 0,88 (0,79-0,97) 1,000 0,88 (0,78-1) 0,998 0,86 (0,7-1,05) 0,993No Ca-inhibitors 0,98 (0,94-1,03) 1,000 0,99 (0,93-1,05) 0,998 0,97 (0,9-1,05) 0,993Aspirin 0,97 (0,91-1,03) 1,000 0,98 (0,91-1,06) 0,998 0,91 (0,8-1,04) 0,993No Aspirin 0,96 (0,91-1,02) 1,000 0,95 (0,88-1,02) 0,998 0,97 (0,89-1,06) 0,993ACE-I/ARB 0,9 (0,83-0,98) 1,000 0,89 (0,82-0,97) 0,998 0,93 (0,85-1,01) 0,993No ACE-I/ARB 0,99 (0,94-1,04) 1,000 0,89 (0,81-0,97) 0,998 0,91 (0,81-1,02) 0,993Statins 0,89 (0,82-0,97) 1,000 0,9 (0,82-1) 0,998 0,86 (0,73-1,03) 0,993No Statins 0,99 (0,94-1,04) 1,000 0,99 (0,93-1,06) 0,998 0,98 (0,9-1,06) 0,993

Summer Olympic Games

Men 1,06 (1,01-1,12) 1,000 1,09 (1,02-1,16) 0,998 1,02 (0,93-1,12) 0,993Women 1 (0,93-1,07) 1,000 0,97 (0,89-1,06) 0,998 1,07 (0,94-1,21) 0,993Age≥75yo 1,04 (0,98-1,11) 1,000 1,03 (0,95-1,1) 0,998 1,09 (0,97-1,23) 0,993Age<75yo 1,04 (0,98-1,1) 1,000 1,06 (0,98-1,14) 0,998 1 (0,91-1,1) 0,993Current Smoker 1,08 (0,99-1,19) 1,000 1,06 (0,93-1,2) 0,998 1,12 (0,97-1,3) 0,993Non Smoker 1,02 (0,97-1,07) 1,000 1,02 (0,97-1,08) 0,998 1,01 (0,95-1,08) 0,993Diabetes 1,04 (0,95-1,14) 1,000 1,01 (0,91-1,12) 0,998 1,14 (0,95-1,36) 0,993No Diabetes 1,04 (0,99-1,09) 1,000 1,05 (0,99-1,12) 0,998 1,02 (0,94-1,1) 0,993Hypertension 1,01 (0,94-1,07) 1,000 1 (0,93-1,08) 0,998 1,02 (0,91-1,15) 0,993No Hypertension 1,06 (1-1,12) 1,000 1,06 (0,99-1,14) 0,998 1,06 (0,96-1,16) 0,993CAD 1,04 (0,97-1,12) 1,000 1,04 (0,97-1,12) 0,998 1,03 (0,96-1,11) 0,993No CAD 1,04 (0,99-1,1) 1,000 1,03 (0,96-1,1) 0,998 1,04 (0,96-1,13) 0,993Beta-blockers 1,06 (0,99-1,13) 1,000 1,06 (0,99-1,15) 0,998 1,03 (0,9-1,17) 0,993No Beta-blockers 1,03 (0,97-1,09) 1,000 1,02 (0,95-1,09) 0,998 1,04 (0,95-1,14) 0,993Ca-inhibitors 1,1 (1-1,22) 1,000 1,13 (1-1,27) 0,998 1,05 (0,87-1,26) 0,993No Ca-inhibitors 1,03 (0,98-1,08) 1,000 1,02 (0,96-1,08) 0,998 1,04 (0,96-1,12) 0,993Aspirin 1,04 (0,97-1,11) 1,000 1,04 (0,96-1,12) 0,998 1,03 (0,9-1,18) 0,993No Aspirin 1,04 (0,99-1,1) 1,000 1,04 (0,97-1,12) 0,998 1,04 (0,95-1,14) 0,993ACE-I/ARB 1,01 (0,93-1,09) 1,000 0,98 (0,91-1,06) 0,998 0,99 (0,91-1,07) 0,993No ACE-I/ARB 1,05 (1-1,11) 1,000 1,33 (1,23-1,44) <0,001 1,28 (1,15-1,43) 0,003Statins 1,06 (0,98-1,16) 1,000 1,06 (0,96-1,16) 0,998 1,09 (0,92-1,29) 0,993No Statins 1,03 (0,98-1,08) 1,000 1,03 (0,97-1,1) 0,998 1,03 (0,94-1,11) 0,993

Men

Monday 1,1 (1,08-1,12) <0,001 1,13 (1,11-1,15) <0,001 1,04 (1,01-1,07) 0,993Tuesday 1,01 (1-1,03) 1,000 1,03 (1,01-1,05) 0,998 0,98 (0,95-1,01) 0,993Wednesday 1,02 (1-1,03) 1,000 1,04 (1,02-1,06) 0,078 0,97 (0,95-1) 0,993Thursday 1,02 (1-1,04) 1,000 1,05 (1,02-1,07) 0,016 0,98 (0,95-1,01) 0,993Friday 1,01 (0,99-1,02) 1,000 1,03 (1-1,05) 0,078 0,97 (0,94-1) 0,993Saturday 0,98 (0,96-0,99) 1,000 0,97 (0,95-0,99) 0,998 0,98 (0,95-1,01) 0,993WomenMonday 1,08 (1,06-1,11) <0,001 1,09 (1,06-1,12) <0,001 1,06 (1,02-1,11) 0,993Tuesday 1,03 (1-1,05) 1,000 1,03 (1,01-1,06) 0,998 1,01 (0,97-1,06) 0,993

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Confidential: For Review OnlyWednesday 1,04 (1,01-1,06) 0,910 1,04 (1,01-1,07) 0,998 1,03 (0,98-1,07) 0,993Thursday 1,04 (1,02-1,07) 0,147 1,05 (1,02-1,08) 0,181 1,03 (0,98-1,07) 0,993Friday 1,04 (1,02-1,07) 0,083 1,05 (1,02-1,08) 0,998 1,04 (0,99-1,08) 0,993Saturday 0,98 (0,96-1) 1,000 0,97 (0,95-1) 0,998 0,99 (0,95-1,03) 0,993Age≥75yoMonday 1,1 (1,08-1,12) <0,001 1,1 (1,07-1,13) <0,001 1,1 (1,05-1,14) 0,003Tuesday 1,04 (1,02-1,06) 0,036 1,03 (1,01-1,06) 0,998 1,06 (1,02-1,11) 0,993Wednesday 1,07 (1,04-1,09) <0,001 1,07 (1,04-1,09) <0,001 1,06 (1,02-1,11) 0,993Thursday 1,08 (1,05-1,1) <0,001 1,08 (1,06-1,11) <0,001 1,06 (1,02-1,1) 0,993Friday 1,06 (1,04-1,08) <0,001 1,07 (1,04-1,09) <0,001 1,05 (1,01-1,1) 0,993Saturday 0,98 (0,96-1) 1,000 0,98 (0,96-1,01) 0,998 0,99 (0,95-1,03) 0,993Age<75yoMonday 1,09 (1,07-1,11) <0,001 1,13 (1,1-1,16) <0,001 1,03 (1-1,06) 0,993Tuesday 1 (0,98-1,02) 1,000 1,03 (1,01-1,06) 0,998 0,95 (0,92-0,98) 0,960Wednesday 0,99 (0,97-1,01) 1,000 1,02 (0,99-1,04) 0,998 0,95 (0,92-0,98) 0,425Thursday 0,99 (0,97-1,01) 1,000 1,01 (0,99-1,04) 0,998 0,96 (0,93-0,98) 0,993Friday 0,99 (0,97-1) 1,000 1 (0,98-1,03) 0,998 0,96 (0,93-0,99) 0,993Saturday 0,97 (0,95-0,99) 0,820 0,96 (0,94-0,99) 0,998 0,98 (0,95-1,01) 0,993Current SmokerMonday 1,04 (1,01-1,08) 1,000 1,07 (1,03-1,12) 0,287 1,01 (0,96-1,06) 0,993Tuesday 0,98 (0,95-1,02) 1,000 1,01 (0,97-1,05) 0,998 0,95 (0,91-1) 0,993Wednesday 1 (0,96-1,03) 1,000 1,04 (0,99-1,08) 0,998 0,95 (0,9-0,99) 0,993Thursday 0,98 (0,95-1,01) 1,000 1,01 (0,97-1,06) 0,998 0,94 (0,89-0,98) 0,993Friday 1 (0,97-1,04) 1,000 1,01 (0,97-1,06) 0,998 0,99 (0,95-1,04) 0,993Saturday 0,98 (0,95-1,02) 1,000 0,98 (0,94-1,02) 0,998 0,99 (0,95-1,04) 0,993Non SmokerMonday 1,11 (1,09-1,12) <0,001 1,13 (1,11-1,15) <0,001 1,06 (1,03-1,09) 0,066Tuesday 1,02 (1,01-1,04) 1,000 1,03 (1,01-1,05) 0,415 1,01 (0,98-1,04) 0,993Wednesday 1,03 (1,01-1,04) 0,406 1,04 (1,02-1,06) 0,066 1 (0,97-1,03) 0,993Thursday 1,04 (1,02-1,05) 0,004 1,05 (1,03-1,07) <0,001 1,01 (0,98-1,04) 0,993Friday 1,02 (1-1,04) 1,000 1,04 (1,02-1,06) 0,066 0,99 (0,96-1,02) 0,993Saturday 0,98 (0,96-0,99) 1,000 0,97 (0,95-0,99) 0,998 0,99 (0,96-1,01) 0,993DiabetesMonday 1,09 (1,06-1,13) <0,001 1,11 (1,07-1,15) <0,001 1,05 (0,99-1,12) 0,993Tuesday 1,06 (1,03-1,09) 0,073 1,06 (1,02-1,1) 0,384 1,06 (1-1,12) 0,993Wednesday 1,03 (1-1,06) 1,000 1,03 (0,99-1,07) 0,998 1,03 (0,97-1,1) 0,993Thursday 1,07 (1,04-1,1) 0,002 1,09 (1,05-1,13) <0,001 1,02 (0,96-1,08) 0,993Friday 1,07 (1,04-1,1) 0,003 1,08 (1,04-1,11) 0,998 1,05 (0,99-1,11) 0,993Saturday 1 (0,97-1,03) 1,000 1,01 (0,98-1,05) 0,998 0,95 (0,89-1) 0,993No DiabetesMonday 1,09 (1,08-1,11) <0,001 1,12 (1,1-1,14) <0,001 1,05 (1,02-1,08) 0,115Tuesday 1,01 (0,99-1,02) 1,000 1,03 (1,01-1,05) 0,998 0,98 (0,95-1,01) 0,993Wednesday 1,02 (1,01-1,04) 1,000 1,05 (1,03-1,07) 0,003 0,98 (0,96-1,01) 0,993Thursday 1,02 (1-1,03) 1,000 1,03 (1,01-1,05) 0,332 0,99 (0,96-1,01) 0,993Friday 1,01 (0,99-1,02) 1,000 1,02 (1-1,04) 0,003 0,98 (0,96-1,01) 0,993Saturday 0,97 (0,96-0,99) 0,120 0,96 (0,94-0,98) 0,028 0,99 (0,96-1,02) 0,993

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Confidential: For Review OnlyHypertensionMonday 1,09 (1,07-1,12) <0,001 1,11 (1,08-1,14) <0,001 1,06 (1,02-1,1) 0,993Tuesday 1,04 (1,02-1,06) 0,045 1,04 (1,02-1,07) 0,420 1,04 (1-1,08) 0,993Wednesday 1,04 (1,02-1,06) 0,190 1,04 (1,02-1,07) 0,221 1,02 (0,98-1,06) 0,993Thursday 1,06 (1,04-1,09) <0,001 1,07 (1,05-1,1) <0,001 1,04 (1-1,08) 0,993Friday 1,04 (1,02-1,06) 0,102 1,05 (1,02-1,08) 0,221 1,01 (0,98-1,05) 0,993Saturday 0,99 (0,97-1,01) 1,000 0,99 (0,97-1,02) 0,998 0,99 (0,95-1,02) 0,993No HypertensionMonday 1,09 (1,07-1,11) <0,001 1,12 (1,1-1,15) <0,001 1,05 (1,01-1,08) 0,993Tuesday 1 (0,98-1,02) 1,000 1,03 (1-1,05) 0,998 0,96 (0,93-0,99) 0,993Wednesday 1,01 (0,99-1,03) 1,000 1,04 (1,01-1,06) 0,527 0,97 (0,94-1) 0,993Thursday 1 (0,99-1,02) 1,000 1,03 (1-1,05) 0,998 0,97 (0,94-1) 0,993Friday 1,01 (0,99-1,02) 1,000 1,02 (1-1,05) 0,527 0,98 (0,95-1,01) 0,993Saturday 0,97 (0,95-0,99) 0,329 0,96 (0,94-0,98) 0,243 0,98 (0,95-1,01) 0,993CADMonday 1,08 (1,05-1,1) <0,001 1,08 (1,05-1,1) <0,001 1,08 (1,03-1,14) 0,993Tuesday 1,02 (0,99-1,04) 1,000 1,02 (1-1,05) 0,998 1 (0,95-1,05) 0,993Wednesday 1,02 (1-1,05) 1,000 1,03 (1-1,05) 0,998 1,01 (0,96-1,06) 0,993Thursday 1,04 (1,02-1,07) 0,210 1,05 (1,02-1,08) 0,155 1,02 (0,97-1,07) 0,993Friday 1,04 (1,02-1,07) 0,168 1,05 (1,02-1,07) 0,998 1,03 (0,98-1,08) 0,993Saturday 0,98 (0,96-1,01) 1,000 0,98 (0,96-1,01) 0,998 0,99 (0,94-1,04) 0,993No CADMonday 1,1 (1,08-1,12) <0,001 1,14 (1,12-1,17) <0,001 1,04 (1,02-1,07) 0,993Tuesday 1,02 (1-1,04) 1,000 1,04 (1,02-1,06) 0,161 0,99 (0,96-1,02) 0,993Wednesday 1,02 (1,01-1,04) 1,000 1,05 (1,03-1,08) 0,003 0,98 (0,96-1,01) 0,993Thursday 1,02 (1-1,04) 1,000 1,05 (1,02-1,07) 0,019 0,99 (0,96-1,01) 0,993Friday 1,01 (0,99-1,03) 1,000 1,03 (1-1,05) 0,003 0,98 (0,96-1,01) 0,993Saturday 0,97 (0,96-0,99) 0,805 0,97 (0,95-0,99) 0,998 0,98 (0,95-1,01) 0,993Beta-blockersMonday 1,1 (1,07-1,12) <0,001 1,1 (1,07-1,13) <0,001 1,09 (1,04-1,13) 0,107Tuesday 1,04 (1,02-1,06) 0,237 1,04 (1,01-1,07) 0,603 1,03 (0,99-1,08) 0,993Wednesday 1,05 (1,03-1,07) 0,007 1,05 (1,02-1,08) 0,035 1,04 (1-1,09) 0,993Thursday 1,06 (1,03-1,08) <0,001 1,06 (1,04-1,09) <0,001 1,04 (0,99-1,08) 0,993Friday 1,05 (1,03-1,07) 0,009 1,05 (1,02-1,08) 0,035 1,04 (0,99-1,08) 0,993Saturday 0,99 (0,97-1,02) 1,000 0,99 (0,97-1,02) 0,998 1 (0,96-1,05) 0,993No Beta-blockersMonday 1,09 (1,07-1,11) <0,001 1,13 (1,1-1,16) <0,001 1,04 (1,01-1,07) 0,993Tuesday 1,01 (0,99-1,02) 1,000 1,03 (1-1,05) 0,998 0,98 (0,95-1) 0,993Wednesday 1,01 (0,99-1,02) 1,000 1,03 (1,01-1,06) 0,998 0,97 (0,94-1) 0,993Thursday 1,01 (0,99-1,03) 1,000 1,03 (1,01-1,06) 0,998 0,98 (0,95-1) 0,993Friday 1 (0,98-1,02) 1,000 1,02 (1-1,04) 0,998 0,97 (0,95-1) 0,993Saturday 0,96 (0,95-0,98) 0,056 0,96 (0,93-0,98) 0,149 0,98 (0,95-1) 0,993Ca-inhibitorsMonday 1,06 (1,03-1,1) 0,058 1,07 (1,03-1,11) 0,218 1,06 (0,99-1,12) 0,993Tuesday 1,01 (0,97-1,04) 1,000 1,01 (0,97-1,05) 0,998 1 (0,94-1,07) 0,993Wednesday 1,02 (0,98-1,05) 1,000 1,02 (0,98-1,06) 0,998 1,02 (0,96-1,09) 0,993

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Confidential: For Review OnlyThursday 1,04 (1-1,07) 1,000 1,05 (1,01-1,09) 0,998 1,01 (0,95-1,07) 0,993Friday 1,04 (1-1,07) 1,000 1,04 (1-1,08) 0,998 1,02 (0,96-1,09) 0,993Saturday 0,98 (0,95-1,01) 1,000 0,98 (0,95-1,02) 0,998 0,96 (0,9-1,03) 0,993No Ca-inhibitorsMonday 1,1 (1,08-1,12) <0,001 1,13 (1,11-1,15) <0,001 1,05 (1,02-1,08) 0,104Tuesday 1,02 (1,01-1,04) 1,000 1,04 (1,02-1,06) 0,027 0,99 (0,97-1,02) 0,993Wednesday 1,03 (1,01-1,04) 0,510 1,05 (1,03-1,07) 0,001 0,99 (0,96-1,01) 0,993Thursday 1,03 (1,01-1,04) 0,200 1,05 (1,03-1,07) 0,001 0,99 (0,97-1,02) 0,993Friday 1,02 (1-1,03) 1,000 1,03 (1,01-1,05) 0,001 0,99 (0,96-1,01) 0,993Saturday 0,98 (0,96-0,99) 0,834 0,97 (0,95-0,99) 0,807 0,99 (0,96-1,01) 0,993AspirinMonday 1,09 (1,07-1,11) <0,001 1,09 (1,07-1,12) <0,001 1,07 (1,03-1,12) 0,709Tuesday 1,04 (1,01-1,06) 0,401 1,04 (1,02-1,07) 0,483 1,02 (0,98-1,07) 0,993Wednesday 1,04 (1,02-1,06) 0,045 1,05 (1,02-1,07) 0,044 1,02 (0,98-1,07) 0,993Thursday 1,06 (1,04-1,08) <0,001 1,06 (1,04-1,09) 0,001 1,06 (1,01-1,1) 0,993Friday 1,05 (1,03-1,07) 0,002 1,05 (1,03-1,08) 0,044 1,04 (0,99-1,08) 0,993Saturday 0,98 (0,96-1,01) 1,000 0,98 (0,96-1,01) 0,998 0,99 (0,94-1,03) 0,993No AspirinMonday 1,1 (1,08-1,12) <0,001 1,14 (1,11-1,16) <0,001 1,04 (1,01-1,07) 0,993Tuesday 1,01 (0,99-1,03) 1,000 1,03 (1-1,05) 0,998 0,98 (0,95-1,01) 0,993Wednesday 1,01 (0,99-1,03) 1,000 1,03 (1,01-1,06) 0,998 0,98 (0,95-1) 0,993Thursday 1,01 (0,99-1,02) 1,000 1,03 (1,01-1,06) 0,998 0,97 (0,94-0,99) 0,993Friday 1 (0,98-1,02) 1,000 1,01 (0,99-1,04) 0,998 0,97 (0,95-1) 0,993Saturday 0,97 (0,95-0,99) 0,670 0,96 (0,94-0,99) 0,718 0,98 (0,96-1,01) 0,993ACE-I/ARBMonday 1,1 (1,07-1,12) <0,001 1,1 (1,07-1,13) <0,001 1,07 (1,02-1,13) 0,993Tuesday 1,04 (1,02-1,07) 0,505 1,03 (1-1,06) 0,998 1,07 (1,02-1,12) 0,993Wednesday 1,04 (1,01-1,06) 1,000 1,04 (1,01-1,07) 0,998 1,03 (0,98-1,08) 0,993Thursday 1,04 (1,02-1,07) 0,327 1,05 (1,02-1,08) 0,152 1,01 (0,96-1,07) 0,993Friday 1,03 (1-1,06) 1,000 1,03 (1,01-1,06) 0,998 1,01 (0,96-1,07) 0,993Saturday 0,98 (0,96-1,01) 1,000 0,98 (0,96-1,01) 0,998 0,98 (0,93-1,03) 0,993No ACE-I/ARBMonday 1,09 (1,07-1,11) <0,001 1,12 (1,1-1,15) <0,001 1,05 (1,02-1,07) 0,756Tuesday 1,01 (0,99-1,03) 1,000 1,03 (1,01-1,06) 0,814 0,97 (0,95-1) 0,993Wednesday 1,02 (1-1,04) 1,000 1,04 (1,02-1,07) 0,040 0,98 (0,95-1,01) 0,993Thursday 1,02 (1,01-1,04) 1,000 1,05 (1,02-1,07) 0,018 0,99 (0,96-1,02) 0,993Friday 1,02 (1-1,03) 1,000 1,03 (1,01-1,06) 0,040 0,99 (0,96-1,01) 0,993Saturday 0,97 (0,96-0,99) 0,805 0,97 (0,95-0,99) 0,998 0,98 (0,96-1,01) 0,993StatinsMonday 1,09 (1,06-1,12) <0,001 1,11 (1,07-1,14) <0,001 1,05 (0,99-1,11) 0,993Tuesday 1,05 (1,02-1,08) 0,153 1,05 (1,02-1,08) 0,398 1,04 (0,99-1,1) 0,993Wednesday 1,04 (1,02-1,07) 0,548 1,05 (1,02-1,08) 0,938 1,03 (0,98-1,09) 0,993Thursday 1,05 (1,03-1,08) 0,051 1,06 (1,03-1,1) 0,042 1,03 (0,97-1,09) 0,993Friday 1,05 (1,02-1,08) 0,099 1,06 (1,03-1,1) 0,938 1,01 (0,95-1,07) 0,993Saturday 0,98 (0,95-1) 1,000 0,97 (0,94-1) 0,998 0,99 (0,94-1,05) 0,993No Statins

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Confidential: For Review OnlyMonday 1,09 (1,08-1,11) <0,001 1,12 (1,1-1,14) <0,001 1,05 (1,02-1,08) 0,100Tuesday 1,01 (0,99-1,02) 1,000 1,02 (1-1,05) 0,998 0,98 (0,96-1,01) 0,993Wednesday 1,02 (1-1,03) 1,000 1,04 (1,02-1,06) 0,111 0,98 (0,96-1,01) 0,993Thursday 1,02 (1-1,04) 1,000 1,04 (1,02-1,06) 0,041 0,99 (0,96-1,01) 0,993Friday 1,01 (0,99-1,03) 1,000 1,02 (1-1,04) 0,111 0,99 (0,96-1,02) 0,993Saturday 0,98 (0,96-0,99) 1,000 0,97 (0,95-0,99) 0,998 0,98 (0,96-1,01) 0,993

Men 1 1 1

01:00 0,89 (0,86-0,93) <0,001 0,88 (0,84-0,92) <0,001 1,01 (0,95-1,08) 0,99302:00 0,94 (0,91-0,98) 0,406 0,92 (0,88-0,96) 0,030 1,07 (1-1,14) 0,99303:00 0,93 (0,9-0,97) 0,042 0,9 (0,86-0,94) 0,001 1,05 (0,99-1,12) 0,99304:00 0,88 (0,85-0,91) <0,001 0,86 (0,82-0,89) <0,001 1,04 (0,98-1,11) 0,99305:00 0,85 (0,82-0,88) <0,001 0,82 (0,78-0,86) <0,001 1,04 (0,98-1,11) 0,99306:00 0,96 (0,92-0,99) 1,000 0,9 (0,86-0,94) 0,001 1,06 (1-1,13) 0,99307:00 1,12 (1,09-1,16) <0,001 1,03 (0,99-1,07) 0,998 1,15 (1,08-1,22) 0,00408:00 1,63 (1,58-1,68) <0,001 1,45 (1,4-1,5) <0,001 1,33 (1,26-1,4) <0,00109:00 1,24 (1,2-1,28) <0,001 1,1 (1,05-1,14) 0,003 1,26 (1,19-1,33) <0,00110:00 1,33 (1,28-1,37) <0,001 1,14 (1,1-1,19) <0,001 1,32 (1,25-1,39) <0,00111:00 1,08 (1,05-1,12) 0,001 0,96 (0,92-1) 0,998 1,25 (1,18-1,33) <0,00112:00 1,28 (1,24-1,32) <0,001 1,15 (1,1-1,19) <0,001 1,25 (1,18-1,32) <0,00113:00 0,97 (0,94-1,01) 1,000 0,88 (0,84-0,92) <0,001 1,17 (1,1-1,24) <0,00114:00 1,01 (0,98-1,05) 1,000 0,92 (0,88-0,96) 0,035 1,16 (1,1-1,24) <0,00115:00 1,02 (0,98-1,05) 1,000 0,94 (0,9-0,98) 0,998 1,12 (1,05-1,18) 0,23816:00 0,93 (0,9-0,96) 0,016 0,87 (0,83-0,91) <0,001 1,1 (1,04-1,17) 0,99317:00 0,86 (0,83-0,89) <0,001 0,81 (0,77-0,85) <0,001 1,06 (1-1,13) 0,99318:00 0,88 (0,85-0,92) <0,001 0,85 (0,81-0,89) <0,001 1,03 (0,97-1,1) 0,99319:00 0,85 (0,82-0,88) <0,001 0,82 (0,78-0,86) <0,001 1,02 (0,95-1,08) 0,99320:00 0,94 (0,91-0,98) 0,433 0,92 (0,88-0,96) 0,023 1 (0,94-1,07) 0,99321:00 0,87 (0,84-0,91) <0,001 0,85 (0,81-0,88) <0,001 1,01 (0,94-1,07) 0,99322:00 0,93 (0,89-0,96) 0,006 0,9 (0,86-0,94) <0,001 1,01 (0,95-1,07) 0,99323:00 0,96 (0,92-0,99) 1,000 0,93 (0,89-0,97) 0,113 1,07 (1,01-1,14) 0,993

Women 1 1 1

01:00 0,87 (0,83-0,91) <0,001 0,88 (0,83-0,93) 0,004 0,93 (0,85-1,02) 0,99302:00 0,87 (0,83-0,91) <0,001 0,88 (0,83-0,93) 0,001 0,92 (0,84-1) 0,99303:00 0,87 (0,83-0,91) <0,001 0,86 (0,82-0,91) <0,001 0,95 (0,87-1,03) 0,99304:00 0,83 (0,79-0,87) <0,001 0,85 (0,8-0,9) <0,001 0,91 (0,83-0,99) 0,99305:00 0,79 (0,75-0,83) <0,001 0,8 (0,76-0,85) <0,001 0,9 (0,82-0,98) 0,99306:00 0,93 (0,89-0,98) 0,820 0,9 (0,86-0,95) 0,107 1 (0,92-1,09) 0,99307:00 1,05 (1-1,09) 1,000 0,98 (0,93-1,04) 0,998 1,03 (0,96-1,12) 0,99308:00 1,51 (1,45-1,57) <0,001 1,37 (1,31-1,43) <0,001 1,19 (1,1-1,28) 0,00409:00 1,05 (1,01-1,1) 1,000 0,95 (0,9-1) 0,998 1,06 (0,98-1,14) 0,99310:00 1,1 (1,05-1,14) 0,010 0,97 (0,93-1,03) 0,998 1,06 (0,98-1,15) 0,99311:00 0,85 (0,82-0,89) <0,001 0,79 (0,74-0,83) <0,001 0,96 (0,89-1,04) 0,99312:00 1,14 (1,09-1,19) <0,001 1,06 (1,01-1,12) 0,998 1,06 (0,98-1,14) 0,99313:00 0,81 (0,77-0,85) <0,001 0,8 (0,75-0,84) <0,001 0,88 (0,81-0,95) 0,99314:00 0,87 (0,83-0,91) <0,001 0,84 (0,79-0,89) <0,001 0,93 (0,85-1,01) 0,993

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Confidential: For Review Only15:00 0,97 (0,93-1,02) 1,000 0,93 (0,88-0,98) 0,998 1,03 (0,95-1,11) 0,99316:00 0,86 (0,83-0,91) <0,001 0,86 (0,81-0,91) <0,001 0,95 (0,87-1,03) 0,99317:00 0,83 (0,79-0,87) <0,001 0,86 (0,81-0,91) <0,001 0,9 (0,82-0,98) 0,99318:00 0,9 (0,86-0,94) 0,003 0,9 (0,85-0,95) 0,044 1 (0,92-1,09) 0,99319:00 0,87 (0,83-0,91) <0,001 0,88 (0,83-0,93) 0,002 0,97 (0,89-1,06) 0,99320:00 1,03 (0,99-1,08) 1,000 1,03 (0,98-1,08) 0,998 1,04 (0,95-1,13) 0,99321:00 0,91 (0,87-0,96) 0,050 0,93 (0,88-0,98) 0,998 0,96 (0,88-1,05) 0,99322:00 0,98 (0,94-1,03) 1,000 0,98 (0,93-1,03) 0,998 1,01 (0,93-1,1) 0,99323:00 0,89 (0,85-0,94) 0,001 0,91 (0,86-0,96) 0,130 0,91 (0,83-0,99) 0,993

Age≥75yo 1 1 1

01:00 0,87 (0,83-0,9) <0,001 0,88 (0,84-0,93) <0,001 0,93 (0,86-1,01) 0,99302:00 0,9 (0,87-0,94) <0,001 0,91 (0,87-0,96) 0,044 0,96 (0,89-1,05) 0,99303:00 0,89 (0,86-0,93) <0,001 0,9 (0,86-0,94) 0,003 0,94 (0,87-1,03) 0,99304:00 0,83 (0,79-0,86) <0,001 0,85 (0,81-0,89) <0,001 0,91 (0,84-0,99) 0,99305:00 0,8 (0,77-0,84) <0,001 0,81 (0,78-0,86) <0,001 0,95 (0,88-1,03) 0,99306:00 0,91 (0,88-0,95) 0,004 0,9 (0,86-0,95) 0,005 0,98 (0,91-1,06) 0,99307:00 1,02 (0,98-1,06) 1,000 0,97 (0,92-1,01) 0,998 1,04 (0,96-1,12) 0,99308:00 1,53 (1,48-1,58) <0,001 1,35 (1,3-1,41) <0,001 1,34 (1,25-1,43) <0,00109:00 1,01 (0,97-1,04) 1,000 0,9 (0,86-0,94) 0,002 1,1 (1,02-1,19) 0,99310:00 1,05 (1,02-1,09) 1,000 0,93 (0,89-0,97) 0,423 1,11 (1,04-1,2) 0,99311:00 0,81 (0,78-0,84) <0,001 0,74 (0,7-0,77) <0,001 1,03 (0,95-1,11) 0,99312:00 1,06 (1,02-1,1) 0,505 0,97 (0,93-1,01) 0,998 1,09 (1,02-1,18) 0,99313:00 0,75 (0,72-0,78) <0,001 0,72 (0,69-0,76) <0,001 0,9 (0,83-0,98) 0,99314:00 0,79 (0,75-0,82) <0,001 0,75 (0,71-0,78) <0,001 0,92 (0,85-0,99) 0,99315:00 0,85 (0,82-0,88) <0,001 0,81 (0,77-0,84) <0,001 0,98 (0,91-1,06) 0,99316:00 0,77 (0,74-0,81) <0,001 0,75 (0,72-0,79) <0,001 0,94 (0,87-1,02) 0,99317:00 0,73 (0,7-0,77) <0,001 0,74 (0,71-0,78) <0,001 0,87 (0,8-0,95) 0,89718:00 0,81 (0,78-0,84) <0,001 0,81 (0,77-0,85) <0,001 0,94 (0,87-1,02) 0,99319:00 0,76 (0,73-0,79) <0,001 0,76 (0,72-0,8) <0,001 0,91 (0,83-0,99) 0,99320:00 0,93 (0,89-0,96) 0,054 0,93 (0,89-0,97) 0,252 0,95 (0,88-1,03) 0,99321:00 0,87 (0,84-0,91) <0,001 0,88 (0,84-0,92) <0,001 0,95 (0,87-1,03) 0,99322:00 0,92 (0,88-0,95) 0,004 0,91 (0,87-0,95) 0,018 0,97 (0,89-1,05) 0,99323:00 0,89 (0,85-0,92) <0,001 0,92 (0,88-0,96) 0,060 0,86 (0,79-0,94) 0,431

Age<75yo 1 1 1

01:00 0,9 (0,87-0,94) <0,001 0,88 (0,83-0,92) <0,001 1,02 (0,95-1,09) 0,99302:00 0,93 (0,89-0,97) 0,096 0,89 (0,85-0,93) 0,001 1,05 (0,98-1,12) 0,99303:00 0,93 (0,89-0,96) 0,081 0,87 (0,83-0,91) <0,001 1,06 (1-1,14) 0,99304:00 0,89 (0,86-0,93) <0,001 0,86 (0,81-0,9) <0,001 1,05 (0,98-1,12) 0,99305:00 0,85 (0,82-0,89) <0,001 0,81 (0,76-0,85) <0,001 1,02 (0,95-1,09) 0,99306:00 0,98 (0,94-1,02) 1,000 0,9 (0,86-0,95) 0,013 1,08 (1,01-1,15) 0,99307:00 1,17 (1,13-1,21) <0,001 1,07 (1,02-1,12) 0,969 1,15 (1,08-1,22) 0,00508:00 1,64 (1,58-1,69) <0,001 1,5 (1,44-1,56) <0,001 1,24 (1,17-1,31) <0,00109:00 1,34 (1,29-1,39) <0,001 1,21 (1,15-1,26) <0,001 1,24 (1,17-1,31) <0,00110:00 1,43 (1,38-1,48) <0,001 1,25 (1,2-1,31) <0,001 1,3 (1,23-1,38) <0,00111:00 1,19 (1,14-1,23) <0,001 1,08 (1,03-1,13) 0,714 1,23 (1,16-1,3) <0,00112:00 1,39 (1,35-1,44) <0,001 1,29 (1,23-1,35) <0,001 1,24 (1,17-1,31) <0,001

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Confidential: For Review Only13:00 1,08 (1,04-1,12) 0,033 0,99 (0,94-1,04) 0,998 1,17 (1,1-1,25) <0,00114:00 1,14 (1,1-1,18) <0,001 1,06 (1,01-1,11) 0,998 1,19 (1,12-1,26) <0,00115:00 1,15 (1,11-1,19) <0,001 1,09 (1,04-1,15) 0,071 1,15 (1,09-1,23) 0,00316:00 1,04 (1-1,08) 1,000 1 (0,95-1,05) 0,998 1,12 (1,05-1,19) 0,43417:00 0,96 (0,93-1) 1,000 0,93 (0,88-0,97) 0,998 1,09 (1,02-1,16) 0,99318:00 0,97 (0,93-1,01) 1,000 0,94 (0,89-0,99) 0,998 1,07 (1,01-1,14) 0,99319:00 0,96 (0,92-0,99) 1,000 0,94 (0,89-0,99) 0,998 1,06 (1-1,13) 0,99320:00 1,03 (0,99-1,07) 1,000 1 (0,96-1,05) 0,998 1,06 (0,99-1,13) 0,99321:00 0,91 (0,87-0,95) 0,002 0,88 (0,84-0,92) <0,001 1,02 (0,95-1,09) 0,99322:00 0,98 (0,94-1,02) 1,000 0,95 (0,91-1) 0,998 1,04 (0,97-1,11) 0,99323:00 0,98 (0,94-1,02) 1,000 0,92 (0,88-0,97) 0,323 1,11 (1,04-1,19) 0,718

Current smoker 1 1 1

01:00 0,92 (0,87-0,98) 1,000 0,88 (0,81-0,96) 0,998 1,04 (0,94-1,15) 0,99302:00 0,96 (0,91-1,03) 1,000 0,92 (0,84-0,99) 0,998 1,07 (0,97-1,17) 0,99303:00 0,91 (0,86-0,97) 1,000 0,88 (0,81-0,96) 0,998 0,97 (0,88-1,08) 0,99304:00 0,86 (0,8-0,91) 0,002 0,82 (0,75-0,89) 0,002 0,97 (0,88-1,08) 0,99305:00 0,86 (0,8-0,92) 0,002 0,81 (0,74-0,88) 0,001 0,98 (0,88-1,08) 0,99306:00 0,92 (0,86-0,98) 1,000 0,82 (0,75-0,89) 0,001 1,01 (0,92-1,11) 0,99307:00 1,05 (0,99-1,12) 1,000 0,98 (0,9-1,06) 0,998 0,98 (0,89-1,08) 0,99308:00 1,44 (1,36-1,52) <0,001 1,31 (1,22-1,4) <0,001 1,09 (1-1,19) 0,99309:00 1,14 (1,08-1,21) 0,006 1,01 (0,94-1,09) 0,998 1,04 (0,95-1,13) 0,99310:00 1,25 (1,18-1,32) <0,001 1,11 (1,03-1,2) 0,998 1,07 (0,98-1,17) 0,99311:00 1,07 (1-1,13) 1,000 0,94 (0,86-1,02) 0,998 1,07 (0,98-1,17) 0,99312:00 1,3 (1,22-1,37) <0,001 1,19 (1,1-1,28) 0,004 1,13 (1,04-1,24) 0,99313:00 1,03 (0,97-1,09) 1,000 0,9 (0,83-0,98) 0,998 1,1 (1-1,21) 0,99314:00 1,08 (1,02-1,15) 1,000 0,96 (0,89-1,05) 0,998 1,12 (1,02-1,23) 0,99315:00 1,1 (1,03-1,16) 0,864 0,97 (0,89-1,05) 0,998 1,16 (1,05-1,27) 0,99316:00 0,96 (0,9-1,02) 1,000 0,88 (0,81-0,96) 0,998 1,05 (0,95-1,15) 0,99317:00 0,95 (0,89-1,01) 1,000 0,91 (0,83-0,99) 0,998 1,03 (0,93-1,13) 0,99318:00 0,95 (0,89-1,01) 1,000 0,9 (0,83-0,98) 0,998 1,05 (0,95-1,15) 0,99319:00 0,91 (0,85-0,97) 0,874 0,88 (0,81-0,96) 0,998 0,99 (0,9-1,09) 0,99320:00 1,04 (0,98-1,1) 1,000 1,01 (0,93-1,09) 0,998 1,06 (0,96-1,17) 0,99321:00 0,93 (0,88-1) 1,000 0,89 (0,82-0,97) 0,998 1,04 (0,94-1,14) 0,99322:00 0,98 (0,92-1,04) 1,000 0,95 (0,88-1,03) 0,998 1,03 (0,93-1,13) 0,99323:00 0,99 (0,93-1,06) 1,000 0,91 (0,84-0,99) 0,998 1,13 (1,02-1,24) 0,993

Non-smoker 1 1 1

01:00 0,91 (0,88-0,94) <0,001 0,91 (0,88-0,95) 0,005 0,99 (0,93-1,06) 0,99302:00 0,93 (0,9-0,96) 0,016 0,93 (0,89-0,97) 0,082 1,02 (0,96-1,09) 0,99303:00 0,94 (0,91-0,97) 0,101 0,92 (0,88-0,95) 0,007 1,06 (1-1,13) 0,99304:00 0,89 (0,86-0,92) <0,001 0,89 (0,85-0,92) <0,001 1,04 (0,98-1,11) 0,99305:00 0,86 (0,83-0,89) <0,001 0,84 (0,81-0,88) <0,001 1,04 (0,97-1,1) 0,99306:00 0,99 (0,96-1,03) 1,000 0,96 (0,92-1) 0,998 1,09 (1,02-1,16) 0,99307:00 1,15 (1,12-1,19) <0,001 1,06 (1,02-1,1) 0,434 1,21 (1,14-1,28) <0,00108:00 1,67 (1,63-1,72) <0,001 1,49 (1,45-1,54) <0,001 1,38 (1,3-1,45) <0,00109:00 1,23 (1,2-1,27) <0,001 1,1 (1,06-1,14) 0,001 1,29 (1,22-1,37) <0,00110:00 1,29 (1,25-1,33) <0,001 1,12 (1,08-1,16) <0,001 1,32 (1,25-1,39) <0,001

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Confidential: For Review Only11:00 1,02 (0,99-1,05) 1,000 0,92 (0,88-0,95) 0,006 1,22 (1,15-1,29) <0,00112:00 1,24 (1,21-1,28) <0,001 1,13 (1,09-1,18) <0,001 1,22 (1,15-1,29) <0,00113:00 0,93 (0,9-0,96) 0,007 0,88 (0,84-0,92) <0,001 1,09 (1,03-1,16) 0,99314:00 0,97 (0,94-1,01) 1,000 0,91 (0,88-0,95) 0,002 1,11 (1,04-1,17) 0,51915:00 1,01 (0,98-1,04) 1,000 0,96 (0,92-1) 0,998 1,1 (1,03-1,16) 0,99316:00 0,93 (0,9-0,96) 0,006 0,9 (0,87-0,94) <0,001 1,08 (1,01-1,14) 0,99317:00 0,85 (0,82-0,88) <0,001 0,84 (0,8-0,87) <0,001 1,01 (0,95-1,08) 0,99318:00 0,9 (0,87-0,93) <0,001 0,89 (0,85-0,92) <0,001 1,04 (0,97-1,1) 0,99319:00 0,87 (0,84-0,9) <0,001 0,86 (0,83-0,9) <0,001 1,03 (0,97-1,1) 0,99320:00 0,99 (0,96-1,02) 1,000 0,98 (0,95-1,02) 0,998 1,02 (0,95-1,08) 0,99321:00 0,91 (0,88-0,94) <0,001 0,9 (0,87-0,94) <0,001 1 (0,94-1,07) 0,99322:00 0,97 (0,94-1,01) 1,000 0,96 (0,92-0,99) 0,998 1,04 (0,98-1,11) 0,99323:00 0,95 (0,92-0,98) 0,662 0,95 (0,91-0,99) 0,998 1 (0,94-1,07) 0,993

Diabetes 1 1 1

01:00 0,84 (0,8-0,89) <0,001 0,85 (0,8-0,91) 0,002 0,92 (0,81-1,04) 0,99302:00 0,86 (0,82-0,91) <0,001 0,89 (0,83-0,95) 0,119 0,88 (0,78-1) 0,99303:00 0,82 (0,77-0,87) <0,001 0,82 (0,77-0,88) <0,001 0,89 (0,79-1) 0,99304:00 0,78 (0,74-0,83) <0,001 0,79 (0,74-0,85) <0,001 0,92 (0,81-1,04) 0,99305:00 0,74 (0,69-0,79) <0,001 0,77 (0,71-0,82) <0,001 0,84 (0,74-0,95) 0,99306:00 0,84 (0,8-0,89) <0,001 0,83 (0,78-0,89) <0,001 0,91 (0,81-1,02) 0,99307:00 0,95 (0,9-1) 1,000 0,9 (0,84-0,96) 0,297 0,98 (0,87-1,09) 0,99308:00 1,41 (1,34-1,48) <0,001 1,3 (1,23-1,37) <0,001 1,1 (0,99-1,22) 0,99309:00 0,97 (0,92-1,02) 1,000 0,91 (0,85-0,97) 0,695 0,98 (0,88-1,09) 0,99310:00 1,01 (0,95-1,06) 1,000 0,9 (0,85-0,96) 0,387 1,04 (0,94-1,16) 0,99311:00 0,74 (0,7-0,78) <0,001 0,7 (0,65-0,75) <0,001 0,88 (0,79-0,99) 0,99312:00 1,01 (0,96-1,06) 1,000 0,96 (0,9-1,02) 0,998 0,95 (0,85-1,06) 0,99313:00 0,71 (0,67-0,76) <0,001 0,69 (0,64-0,74) <0,001 0,86 (0,76-0,96) 0,99314:00 0,77 (0,73-0,82) <0,001 0,77 (0,72-0,82) <0,001 0,82 (0,73-0,93) 0,76115:00 0,81 (0,77-0,86) <0,001 0,8 (0,75-0,86) <0,001 0,87 (0,77-0,98) 0,99316:00 0,73 (0,68-0,77) <0,001 0,75 (0,7-0,81) <0,001 0,76 (0,67-0,86) 0,01017:00 0,73 (0,68-0,77) <0,001 0,74 (0,69-0,8) <0,001 0,85 (0,76-0,96) 0,99318:00 0,8 (0,75-0,85) <0,001 0,8 (0,75-0,86) <0,001 0,92 (0,82-1,04) 0,99319:00 0,77 (0,72-0,81) <0,001 0,77 (0,72-0,83) <0,001 0,9 (0,8-1,01) 0,99320:00 0,96 (0,91-1,01) 1,000 0,97 (0,91-1,03) 0,998 0,95 (0,85-1,07) 0,99321:00 0,86 (0,81-0,91) <0,001 0,87 (0,82-0,93) 0,016 0,91 (0,8-1,02) 0,99322:00 0,9 (0,85-0,96) 0,158 0,92 (0,86-0,98) 0,998 0,89 (0,79-1) 0,99323:00 0,89 (0,84-0,94) 0,032 0,91 (0,86-0,97) 0,998 0,89 (0,79-1) 0,993

No Diabetes 1 1 1

01:00 0,9 (0,87-0,93) <0,001 0,89 (0,86-0,93) <0,001 1 (0,94-1,06) 0,99302:00 0,93 (0,91-0,97) 0,017 0,91 (0,88-0,95) 0,002 1,04 (0,99-1,1) 0,99303:00 0,94 (0,91-0,97) 0,061 0,91 (0,88-0,95) 0,002 1,04 (0,99-1,1) 0,99304:00 0,89 (0,86-0,92) <0,001 0,88 (0,84-0,91) <0,001 1,01 (0,96-1,07) 0,99305:00 0,86 (0,83-0,89) <0,001 0,83 (0,8-0,87) <0,001 1,02 (0,97-1,08) 0,99306:00 0,98 (0,95-1,02) 1,000 0,93 (0,9-0,97) 0,137 1,07 (1,01-1,13) 0,99307:00 1,15 (1,11-1,18) <0,001 1,06 (1,02-1,1) 0,527 1,14 (1,08-1,2) 0,00108:00 1,65 (1,6-1,69) <0,001 1,47 (1,42-1,52) <0,001 1,32 (1,26-1,39) <0,001

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Confidential: For Review Only09:00 1,24 (1,2-1,28) <0,001 1,09 (1,05-1,13) 0,001 1,23 (1,17-1,3) <0,00110:00 1,32 (1,28-1,36) <0,001 1,15 (1,11-1,19) <0,001 1,27 (1,21-1,33) <0,00111:00 1,08 (1,05-1,12) <0,001 0,97 (0,93-1) 0,998 1,21 (1,15-1,27) <0,00112:00 1,3 (1,26-1,34) <0,001 1,18 (1,14-1,22) <0,001 1,23 (1,17-1,3) <0,00113:00 0,98 (0,95-1,01) 1,000 0,9 (0,87-0,94) <0,001 1,11 (1,06-1,18) 0,05014:00 1,03 (0,99-1,06) 1,000 0,94 (0,9-0,97) 0,373 1,14 (1,08-1,2) 0,00115:00 1,06 (1,03-1,1) 0,050 0,99 (0,96-1,03) 0,998 1,13 (1,07-1,2) 0,00316:00 0,97 (0,93-1) 1,000 0,91 (0,88-0,95) 0,002 1,11 (1,05-1,18) 0,08817:00 0,89 (0,86-0,92) <0,001 0,86 (0,82-0,89) <0,001 1,04 (0,98-1,09) 0,99318:00 0,92 (0,89-0,95) <0,001 0,9 (0,86-0,93) <0,001 1,04 (0,99-1,1) 0,99319:00 0,89 (0,86-0,92) <0,001 0,87 (0,83-0,9) <0,001 1,02 (0,96-1,08) 0,99320:00 0,99 (0,96-1,02) 1,000 0,96 (0,93-1) 0,998 1,03 (0,97-1,09) 0,99321:00 0,9 (0,87-0,93) <0,001 0,88 (0,85-0,92) <0,001 1,01 (0,95-1,07) 0,99322:00 0,96 (0,93-0,99) 1,000 0,93 (0,9-0,97) 0,157 1,04 (0,98-1,1) 0,99323:00 0,95 (0,92-0,98) 0,389 0,92 (0,89-0,96) 0,018 1,04 (0,98-1,1) 0,993

Hypertension 1 1 1

01:00 0,88 (0,84-0,91) <0,001 0,9 (0,86-0,94) 0,006 0,91 (0,84-0,99) 0,99302:00 0,89 (0,86-0,93) <0,001 0,9 (0,86-0,95) 0,011 0,95 (0,88-1,03) 0,99303:00 0,89 (0,85-0,93) <0,001 0,88 (0,84-0,92) <0,001 0,98 (0,9-1,06) 0,99304:00 0,82 (0,78-0,85) <0,001 0,82 (0,78-0,86) <0,001 0,95 (0,87-1,03) 0,99305:00 0,78 (0,75-0,82) <0,001 0,76 (0,73-0,81) <0,001 0,98 (0,9-1,06) 0,99306:00 0,91 (0,87-0,95) 0,002 0,89 (0,84-0,93) <0,001 0,98 (0,91-1,06) 0,99307:00 1 (0,97-1,04) 1,000 0,94 (0,9-0,99) 0,998 1,02 (0,95-1,1) 0,99308:00 1,49 (1,44-1,55) <0,001 1,36 (1,31-1,42) <0,001 1,18 (1,1-1,26) 0,00309:00 1,05 (1,01-1,09) 1,000 0,96 (0,92-1,01) 0,998 1,06 (0,99-1,14) 0,99310:00 1,1 (1,06-1,15) <0,001 0,98 (0,94-1,02) 0,998 1,11 (1,03-1,19) 0,99311:00 0,85 (0,82-0,88) <0,001 0,79 (0,75-0,83) <0,001 0,98 (0,91-1,06) 0,99312:00 1,1 (1,06-1,15) <0,001 1,02 (0,97-1,06) 0,998 1,08 (1-1,16) 0,99313:00 0,79 (0,75-0,82) <0,001 0,76 (0,72-0,8) <0,001 0,92 (0,85-0,99) 0,99314:00 0,86 (0,82-0,89) <0,001 0,81 (0,77-0,85) <0,001 0,98 (0,91-1,06) 0,99315:00 0,89 (0,85-0,93) <0,001 0,86 (0,82-0,9) <0,001 0,95 (0,88-1,02) 0,99316:00 0,79 (0,76-0,83) <0,001 0,78 (0,74-0,82) <0,001 0,9 (0,83-0,97) 0,99317:00 0,78 (0,74-0,81) <0,001 0,77 (0,73-0,81) <0,001 0,92 (0,85-1) 0,99318:00 0,83 (0,79-0,86) <0,001 0,82 (0,78-0,86) <0,001 0,95 (0,88-1,03) 0,99319:00 0,81 (0,78-0,85) <0,001 0,81 (0,77-0,85) <0,001 0,95 (0,87-1,03) 0,99320:00 0,93 (0,89-0,96) 0,066 0,92 (0,87-0,96) 0,088 0,96 (0,89-1,04) 0,99321:00 0,87 (0,83-0,9) <0,001 0,86 (0,82-0,9) <0,001 0,97 (0,89-1,05) 0,99322:00 0,93 (0,9-0,97) 0,261 0,93 (0,88-0,97) 0,351 0,99 (0,91-1,07) 0,99323:00 0,91 (0,87-0,95) 0,003 0,9 (0,86-0,95) 0,012 0,98 (0,91-1,07) 0,993

No Hypertension 1 1 1

01:00 0,9 (0,86-0,94) <0,001 0,87 (0,83-0,91) <0,001 1,04 (0,97-1,11) 0,99302:00 0,94 (0,91-0,98) 0,805 0,91 (0,87-0,96) 0,049 1,06 (0,99-1,13) 0,99303:00 0,93 (0,9-0,97) 0,161 0,9 (0,85-0,94) 0,004 1,04 (0,97-1,12) 0,99304:00 0,91 (0,87-0,94) <0,001 0,89 (0,85-0,94) 0,003 1,03 (0,96-1,1) 0,99305:00 0,88 (0,84-0,92) <0,001 0,87 (0,82-0,91) <0,001 1,01 (0,94-1,08) 0,99306:00 0,99 (0,95-1,03) 1,000 0,93 (0,88-0,97) 0,512 1,08 (1,01-1,15) 0,993

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Confidential: For Review Only07:00 1,19 (1,15-1,23) <0,001 1,1 (1,05-1,15) 0,010 1,17 (1,1-1,25) <0,00108:00 1,68 (1,63-1,74) <0,001 1,49 (1,43-1,55) <0,001 1,36 (1,28-1,44) <0,00109:00 1,29 (1,25-1,34) <0,001 1,13 (1,08-1,18) <0,001 1,28 (1,21-1,36) <0,00110:00 1,38 (1,33-1,43) <0,001 1,19 (1,14-1,24) <0,001 1,31 (1,24-1,39) <0,00111:00 1,14 (1,1-1,19) <0,001 1 (0,96-1,05) 0,998 1,27 (1,2-1,35) <0,00112:00 1,35 (1,3-1,4) <0,001 1,22 (1,17-1,28) <0,001 1,26 (1,19-1,34) <0,00113:00 1,03 (1-1,07) 1,000 0,94 (0,9-0,99) 0,998 1,17 (1,1-1,25) 0,00114:00 1,06 (1,02-1,1) 0,515 0,97 (0,93-1,02) 0,998 1,16 (1,09-1,23) 0,00415:00 1,11 (1,07-1,15) <0,001 1,02 (0,98-1,07) 0,998 1,19 (1,12-1,27) <0,00116:00 1,01 (0,98-1,05) 1,000 0,96 (0,91-1) 0,998 1,15 (1,08-1,23) 0,01017:00 0,92 (0,88-0,96) 0,015 0,89 (0,84-0,93) 0,001 1,06 (0,99-1,13) 0,99318:00 0,95 (0,91-0,99) 1,000 0,92 (0,87-0,96) 0,193 1,08 (1,01-1,15) 0,99319:00 0,9 (0,86-0,94) <0,001 0,87 (0,83-0,92) <0,001 1,04 (0,97-1,11) 0,99320:00 1,03 (0,99-1,07) 1,000 1,01 (0,97-1,06) 0,998 1,05 (0,98-1,12) 0,99321:00 0,91 (0,88-0,95) 0,002 0,89 (0,85-0,94) 0,002 1,01 (0,94-1,08) 0,99322:00 0,96 (0,92-1) 1,000 0,93 (0,89-0,98) 0,969 1,03 (0,96-1,1) 0,99323:00 0,96 (0,92-1) 1,000 0,94 (0,89-0,98) 0,998 1,04 (0,97-1,11) 0,993

CAD 1 1 1

01:00 0,91 (0,87-0,96) 0,036 0,92 (0,88-0,97) 0,345 1,06 (0,95-1,18) 0,99302:00 0,93 (0,89-0,98) 0,780 0,94 (0,89-0,98) 0,998 1,1 (0,99-1,22) 0,99303:00 0,91 (0,87-0,95) 0,027 0,91 (0,87-0,96) 0,074 1,05 (0,94-1,17) 0,99304:00 0,86 (0,82-0,9) <0,001 0,88 (0,84-0,92) <0,001 1,02 (0,92-1,13) 0,99305:00 0,81 (0,77-0,85) <0,001 0,83 (0,79-0,88) <0,001 1,01 (0,91-1,13) 0,99306:00 0,91 (0,87-0,95) 0,025 0,9 (0,86-0,94) 0,008 1,08 (0,98-1,2) 0,99307:00 1,01 (0,97-1,05) 1,000 0,95 (0,91-1) 0,998 1,13 (1,03-1,25) 0,99308:00 1,38 (1,33-1,44) <0,001 1,25 (1,2-1,3) <0,001 1,2 (1,1-1,32) 0,05909:00 0,94 (0,9-0,98) 0,754 0,87 (0,83-0,91) <0,001 1,08 (0,98-1,19) 0,99310:00 0,97 (0,93-1,01) 1,000 0,87 (0,83-0,91) <0,001 1,11 (1,01-1,22) 0,99311:00 0,74 (0,7-0,77) <0,001 0,71 (0,67-0,74) <0,001 0,98 (0,89-1,09) 0,99312:00 0,93 (0,89-0,97) 0,335 0,87 (0,83-0,91) <0,001 1 (0,9-1,1) 0,99313:00 0,68 (0,65-0,71) <0,001 0,68 (0,65-0,72) <0,001 0,86 (0,78-0,96) 0,99314:00 0,73 (0,7-0,76) <0,001 0,71 (0,67-0,75) <0,001 0,92 (0,83-1,02) 0,99315:00 0,77 (0,74-0,81) <0,001 0,77 (0,73-0,81) <0,001 0,85 (0,77-0,95) 0,99316:00 0,73 (0,7-0,77) <0,001 0,73 (0,69-0,77) <0,001 0,96 (0,87-1,07) 0,99317:00 0,73 (0,7-0,77) <0,001 0,75 (0,71-0,79) <0,001 0,94 (0,85-1,05) 0,99318:00 0,82 (0,78-0,86) <0,001 0,83 (0,79-0,87) <0,001 0,99 (0,89-1,1) 0,99319:00 0,79 (0,75-0,82) <0,001 0,79 (0,75-0,83) <0,001 1,02 (0,92-1,14) 0,99320:00 0,94 (0,9-0,98) 1,000 0,93 (0,89-0,98) 0,998 1,02 (0,92-1,13) 0,99321:00 0,91 (0,87-0,95) 0,018 0,91 (0,87-0,96) 0,068 1,08 (0,97-1,2) 0,99322:00 0,96 (0,92-1) 1,000 0,95 (0,9-1) 0,998 1,09 (0,98-1,21) 0,99323:00 0,98 (0,94-1,02) 1,000 0,98 (0,93-1,03) 0,998 1,11 (1-1,24) 0,993

No CAD 1 1 1

01:00 0,87 (0,84-0,9) <0,001 0,85 (0,81-0,89) <0,001 0,96 (0,9-1,02) 0,99302:00 0,9 (0,87-0,94) <0,001 0,87 (0,84-0,92) <0,001 0,99 (0,93-1,05) 0,99303:00 0,91 (0,88-0,94) <0,001 0,87 (0,83-0,91) <0,001 1,01 (0,95-1,07) 0,99304:00 0,86 (0,83-0,9) <0,001 0,83 (0,79-0,87) <0,001 0,99 (0,93-1,05) 0,993

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Confidential: For Review Only05:00 0,84 (0,81-0,87) <0,001 0,79 (0,75-0,83) <0,001 0,98 (0,93-1,04) 0,99306:00 0,97 (0,94-1) 1,000 0,91 (0,86-0,95) 0,008 1,03 (0,97-1,09) 0,99307:00 1,15 (1,11-1,19) <0,001 1,07 (1,02-1,11) 0,998 1,1 (1,04-1,16) 0,53508:00 1,72 (1,67-1,77) <0,001 1,57 (1,51-1,63) <0,001 1,3 (1,24-1,37) <0,00109:00 1,32 (1,28-1,37) <0,001 1,19 (1,14-1,24) <0,001 1,22 (1,16-1,28) <0,00110:00 1,42 (1,38-1,47) <0,001 1,25 (1,2-1,31) <0,001 1,26 (1,2-1,33) <0,00111:00 1,17 (1,13-1,21) <0,001 1,05 (1-1,1) 0,998 1,2 (1,14-1,26) <0,00112:00 1,42 (1,38-1,47) <0,001 1,32 (1,27-1,38) <0,001 1,24 (1,17-1,3) <0,00113:00 1,07 (1,03-1,1) 0,123 0,99 (0,94-1,03) 0,998 1,12 (1,06-1,19) 0,01914:00 1,11 (1,08-1,15) <0,001 1,04 (1-1,09) 0,998 1,13 (1,07-1,19) 0,01315:00 1,15 (1,11-1,19) <0,001 1,08 (1,03-1,13) 0,234 1,15 (1,09-1,22) <0,00116:00 1,02 (0,98-1,05) 1,000 0,99 (0,94-1,03) 0,998 1,07 (1,01-1,13) 0,99317:00 0,92 (0,89-0,96) 0,009 0,89 (0,85-0,94) 0,001 1,02 (0,96-1,08) 0,99318:00 0,94 (0,9-0,97) 0,127 0,9 (0,86-0,94) 0,005 1,03 (0,97-1,09) 0,99319:00 0,9 (0,87-0,94) <0,001 0,89 (0,85-0,93) <0,001 0,99 (0,94-1,05) 0,99320:00 1 (0,97-1,04) 1,000 0,99 (0,94-1,03) 0,998 1,01 (0,96-1,07) 0,99321:00 0,88 (0,84-0,91) <0,001 0,85 (0,81-0,89) <0,001 0,96 (0,91-1,02) 0,99322:00 0,94 (0,9-0,97) 0,138 0,91 (0,87-0,95) 0,022 0,98 (0,93-1,04) 0,99323:00 0,9 (0,87-0,94) <0,001 0,87 (0,83-0,91) <0,001 0,98 (0,93-1,04) 0,993

Beta-blockers 1 1 1

01:00 0,89 (0,85-0,92) <0,001 0,89 (0,85-0,93) 0,001 1 (0,91-1,09) 0,99302:00 0,9 (0,86-0,93) <0,001 0,9 (0,86-0,95) 0,005 0,99 (0,91-1,08) 0,99303:00 0,89 (0,85-0,93) <0,001 0,88 (0,84-0,92) <0,001 1,01 (0,93-1,11) 0,99304:00 0,83 (0,8-0,87) <0,001 0,85 (0,81-0,89) <0,001 1 (0,91-1,09) 0,99305:00 0,79 (0,76-0,83) <0,001 0,8 (0,76-0,84) <0,001 1 (0,92-1,09) 0,99306:00 0,88 (0,84-0,91) <0,001 0,86 (0,82-0,9) <0,001 1,01 (0,93-1,1) 0,99307:00 0,97 (0,93-1,01) 1,000 0,92 (0,88-0,96) 0,060 1,02 (0,94-1,11) 0,99308:00 1,38 (1,33-1,43) <0,001 1,26 (1,21-1,31) <0,001 1,13 (1,05-1,22) 0,99309:00 0,92 (0,88-0,96) 0,009 0,85 (0,81-0,88) <0,001 0,99 (0,92-1,08) 0,99310:00 0,95 (0,91-0,98) 1,000 0,85 (0,81-0,88) <0,001 1,02 (0,95-1,11) 0,99311:00 0,72 (0,69-0,75) <0,001 0,68 (0,65-0,72) <0,001 0,88 (0,81-0,96) 0,99312:00 0,95 (0,91-0,99) 1,000 0,89 (0,85-0,93) <0,001 0,95 (0,88-1,03) 0,99313:00 0,68 (0,65-0,71) <0,001 0,66 (0,63-0,7) <0,001 0,86 (0,79-0,94) 0,37614:00 0,74 (0,71-0,77) <0,001 0,72 (0,69-0,76) <0,001 0,86 (0,79-0,94) 0,62515:00 0,79 (0,76-0,82) <0,001 0,77 (0,73-0,8) <0,001 0,88 (0,81-0,96) 0,99316:00 0,73 (0,7-0,76) <0,001 0,72 (0,68-0,75) <0,001 0,92 (0,84-1) 0,99317:00 0,74 (0,71-0,77) <0,001 0,74 (0,7-0,77) <0,001 0,94 (0,86-1,02) 0,99318:00 0,8 (0,76-0,83) <0,001 0,8 (0,76-0,84) <0,001 0,95 (0,87-1,03) 0,99319:00 0,77 (0,74-0,8) <0,001 0,76 (0,73-0,8) <0,001 0,98 (0,9-1,07) 0,99320:00 0,92 (0,88-0,95) 0,009 0,92 (0,88-0,96) 0,044 0,96 (0,88-1,04) 0,99321:00 0,87 (0,84-0,91) <0,001 0,88 (0,84-0,92) <0,001 0,97 (0,89-1,06) 0,99322:00 0,94 (0,9-0,98) 0,780 0,93 (0,89-0,97) 0,681 1,02 (0,94-1,11) 0,99323:00 0,96 (0,92-1) 1,000 0,96 (0,92-1,01) 0,998 1,05 (0,96-1,14) 0,993

No Beta-blockers 1 1 1

01:00 0,89 (0,85-0,92) <0,001 0,87 (0,83-0,91) <0,001 0,98 (0,91-1,04) 0,99302:00 0,93 (0,9-0,97) 0,169 0,9 (0,86-0,95) 0,014 1,02 (0,96-1,09) 0,993

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Confidential: For Review Only03:00 0,93 (0,89-0,97) 0,101 0,89 (0,85-0,94) 0,004 1,02 (0,95-1,08) 0,99304:00 0,88 (0,85-0,92) <0,001 0,86 (0,82-0,91) <0,001 0,99 (0,93-1,06) 0,99305:00 0,86 (0,83-0,9) <0,001 0,83 (0,78-0,87) <0,001 0,98 (0,92-1,05) 0,99306:00 1,01 (0,97-1,05) 1,000 0,96 (0,91-1) 0,998 1,05 (0,99-1,12) 0,99307:00 1,21 (1,17-1,26) <0,001 1,13 (1,08-1,18) <0,001 1,15 (1,09-1,22) 0,00208:00 1,78 (1,72-1,83) <0,001 1,61 (1,55-1,68) <0,001 1,35 (1,28-1,43) <0,00109:00 1,41 (1,36-1,46) <0,001 1,27 (1,21-1,33) <0,001 1,28 (1,21-1,36) <0,00110:00 1,51 (1,46-1,57) <0,001 1,35 (1,29-1,41) <0,001 1,33 (1,26-1,41) <0,00111:00 1,26 (1,21-1,3) <0,001 1,13 (1,08-1,19) <0,001 1,29 (1,22-1,36) <0,00112:00 1,49 (1,44-1,54) <0,001 1,38 (1,32-1,44) <0,001 1,3 (1,23-1,37) <0,00113:00 1,13 (1,09-1,17) <0,001 1,06 (1,01-1,11) 0,998 1,17 (1,1-1,24) <0,00114:00 1,17 (1,12-1,21) <0,001 1,08 (1,03-1,13) 0,408 1,19 (1,12-1,26) <0,00115:00 1,2 (1,16-1,24) <0,001 1,14 (1,08-1,19) <0,001 1,19 (1,12-1,26) <0,00116:00 1,07 (1,03-1,11) 0,287 1,04 (0,99-1,09) 0,998 1,11 (1,05-1,18) 0,35117:00 0,95 (0,92-0,99) 1,000 0,93 (0,89-0,98) 0,998 1,03 (0,97-1,1) 0,99318:00 0,98 (0,94-1,01) 1,000 0,95 (0,9-1) 0,998 1,06 (1-1,13) 0,99319:00 0,94 (0,9-0,98) 0,562 0,94 (0,89-0,98) 0,998 1,01 (0,95-1,08) 0,99320:00 1,03 (0,99-1,07) 1,000 1,01 (0,97-1,06) 0,998 1,04 (0,98-1,11) 0,99321:00 0,91 (0,87-0,94) <0,001 0,88 (0,83-0,92) <0,001 1 (0,94-1,07) 0,99322:00 0,95 (0,92-0,99) 1,000 0,92 (0,88-0,97) 0,470 1 (0,94-1,07) 0,99323:00 0,91 (0,87-0,94) 0,001 0,87 (0,83-0,91) <0,001 0,99 (0,93-1,06) 0,993

Ca-inhibitor 1 1 1

01:00 0,92 (0,86-0,98) 1,000 0,96 (0,9-1,04) 0,998 0,88 (0,77-1) 0,99302:00 0,92 (0,87-0,98) 1,000 0,93 (0,87-1) 0,998 0,99 (0,87-1,12) 0,99303:00 0,92 (0,86-0,98) 1,000 0,94 (0,87-1,01) 0,998 0,93 (0,81-1,06) 0,99304:00 0,85 (0,79-0,9) <0,001 0,87 (0,81-0,94) 0,116 0,93 (0,82-1,06) 0,99305:00 0,82 (0,77-0,87) <0,001 0,82 (0,76-0,89) <0,001 0,99 (0,87-1,13) 0,99306:00 0,92 (0,86-0,98) 1,000 0,91 (0,85-0,98) 0,998 0,98 (0,86-1,11) 0,99307:00 1 (0,94-1,06) 1,000 0,97 (0,9-1,03) 0,998 0,97 (0,86-1,1) 0,99308:00 1,43 (1,36-1,51) <0,001 1,3 (1,22-1,39) <0,001 1,15 (1,03-1,29) 0,99309:00 1,03 (0,97-1,09) 1,000 0,94 (0,87-1,01) 0,998 1,08 (0,96-1,21) 0,99310:00 1,05 (0,99-1,11) 1,000 0,92 (0,86-0,99) 0,998 1,11 (0,99-1,25) 0,99311:00 0,82 (0,77-0,87) <0,001 0,75 (0,69-0,81) <0,001 1,03 (0,91-1,16) 0,99312:00 1,02 (0,96-1,08) 1,000 0,93 (0,86-0,99) 0,998 1,06 (0,94-1,19) 0,99313:00 0,76 (0,71-0,81) <0,001 0,74 (0,68-0,8) <0,001 0,91 (0,8-1,03) 0,99314:00 0,79 (0,74-0,84) <0,001 0,74 (0,69-0,8) <0,001 0,93 (0,82-1,05) 0,99315:00 0,81 (0,76-0,86) <0,001 0,79 (0,74-0,85) <0,001 0,85 (0,75-0,97) 0,99316:00 0,73 (0,69-0,78) <0,001 0,73 (0,67-0,79) <0,001 0,86 (0,75-0,97) 0,99317:00 0,72 (0,68-0,78) <0,001 0,74 (0,68-0,8) <0,001 0,84 (0,73-0,96) 0,99318:00 0,79 (0,74-0,85) <0,001 0,82 (0,76-0,88) <0,001 0,84 (0,74-0,96) 0,99319:00 0,79 (0,74-0,84) <0,001 0,8 (0,74-0,87) <0,001 0,91 (0,79-1,03) 0,99320:00 0,93 (0,87-0,98) 1,000 0,93 (0,86-1) 0,998 0,94 (0,83-1,07) 0,99321:00 0,88 (0,82-0,93) 0,017 0,9 (0,83-0,96) 0,915 0,91 (0,79-1,03) 0,99322:00 0,95 (0,89-1,01) 1,000 0,96 (0,89-1,03) 0,998 0,94 (0,83-1,07) 0,99323:00 0,95 (0,89-1,01) 1,000 0,96 (0,89-1,03) 0,998 0,98 (0,87-1,12) 0,993

No Ca-inhibitor 1 1 1

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Confidential: For Review Only01:00 0,88 (0,85-0,91) <0,001 0,86 (0,83-0,89) <0,001 1 (0,95-1,06) 0,99302:00 0,91 (0,89-0,94) <0,001 0,89 (0,86-0,93) <0,001 1,02 (0,96-1,08) 0,99303:00 0,91 (0,88-0,94) <0,001 0,87 (0,84-0,91) <0,001 1,03 (0,98-1,09) 0,99304:00 0,86 (0,84-0,89) <0,001 0,85 (0,82-0,88) <0,001 1,01 (0,95-1,06) 0,99305:00 0,83 (0,8-0,86) <0,001 0,81 (0,78-0,84) <0,001 0,99 (0,93-1,05) 0,99306:00 0,95 (0,92-0,98) 0,770 0,9 (0,87-0,93) <0,001 1,05 (1-1,11) 0,99307:00 1,12 (1,09-1,15) <0,001 1,03 (0,99-1,06) 0,998 1,13 (1,07-1,19) 0,00208:00 1,62 (1,58-1,67) <0,001 1,45 (1,41-1,5) <0,001 1,3 (1,24-1,37) <0,00109:00 1,21 (1,17-1,24) <0,001 1,07 (1,03-1,11) 0,083 1,2 (1,15-1,27) <0,00110:00 1,29 (1,25-1,32) <0,001 1,12 (1,08-1,16) <0,001 1,25 (1,19-1,31) <0,00111:00 1,04 (1,01-1,07) 1,000 0,93 (0,9-0,97) 0,063 1,17 (1,11-1,23) <0,00112:00 1,28 (1,24-1,31) <0,001 1,17 (1,13-1,21) <0,001 1,2 (1,14-1,26) <0,00113:00 0,95 (0,92-0,98) 0,478 0,88 (0,84-0,91) <0,001 1,09 (1,04-1,15) 0,68414:00 1 (0,97-1,03) 1,000 0,93 (0,89-0,96) 0,037 1,11 (1,05-1,17) 0,08815:00 1,05 (1,02-1,08) 0,960 0,98 (0,94-1,01) 0,998 1,13 (1,07-1,19) 0,00516:00 0,95 (0,92-0,98) 0,231 0,9 (0,87-0,94) <0,001 1,08 (1,03-1,14) 0,99317:00 0,88 (0,85-0,91) <0,001 0,85 (0,82-0,88) <0,001 1,03 (0,98-1,09) 0,99318:00 0,91 (0,89-0,94) <0,001 0,88 (0,85-0,92) <0,001 1,05 (1-1,11) 0,99319:00 0,87 (0,85-0,9) <0,001 0,85 (0,82-0,89) <0,001 1,02 (0,96-1,08) 0,99320:00 0,99 (0,96-1,02) 1,000 0,97 (0,93-1,01) 0,998 1,03 (0,97-1,09) 0,99321:00 0,89 (0,87-0,92) <0,001 0,87 (0,84-0,91) <0,001 1,01 (0,95-1,06) 0,99322:00 0,95 (0,92-0,98) 0,174 0,92 (0,89-0,96) 0,005 1,02 (0,97-1,08) 0,99323:00 0,93 (0,9-0,96) 0,003 0,91 (0,87-0,94) <0,001 1,02 (0,96-1,08) 0,993

Aspirin 1 1 1

01:00 0,87 (0,84-0,91) <0,001 0,88 (0,84-0,92) <0,001 0,97 (0,88-1,06) 0,99302:00 0,89 (0,86-0,93) <0,001 0,9 (0,86-0,94) 0,001 1 (0,91-1,09) 0,99303:00 0,88 (0,85-0,92) <0,001 0,88 (0,84-0,92) <0,001 0,99 (0,91-1,09) 0,99304:00 0,81 (0,78-0,84) <0,001 0,82 (0,79-0,86) <0,001 0,96 (0,88-1,05) 0,99305:00 0,77 (0,74-0,8) <0,001 0,78 (0,75-0,82) <0,001 0,96 (0,87-1,05) 0,99306:00 0,88 (0,85-0,92) <0,001 0,87 (0,83-0,91) <0,001 1,02 (0,93-1,11) 0,99307:00 1,01 (0,97-1,05) 1,000 0,95 (0,91-0,99) 0,998 1,09 (1,01-1,19) 0,99308:00 1,42 (1,37-1,47) <0,001 1,28 (1,23-1,33) <0,001 1,22 (1,13-1,31) <0,00109:00 0,96 (0,92-0,99) 1,000 0,89 (0,85-0,93) <0,001 1,03 (0,95-1,11) 0,99310:00 0,98 (0,95-1,02) 1,000 0,89 (0,85-0,93) <0,001 1,05 (0,97-1,14) 0,99311:00 0,75 (0,72-0,78) <0,001 0,71 (0,68-0,75) <0,001 0,93 (0,85-1,01) 0,99312:00 0,97 (0,93-1,01) 1,000 0,91 (0,87-0,95) 0,004 0,98 (0,9-1,07) 0,99313:00 0,69 (0,67-0,73) <0,001 0,69 (0,66-0,73) <0,001 0,83 (0,76-0,91) 0,03814:00 0,75 (0,72-0,78) <0,001 0,74 (0,7-0,77) <0,001 0,87 (0,8-0,95) 0,99315:00 0,78 (0,75-0,81) <0,001 0,77 (0,74-0,81) <0,001 0,83 (0,76-0,91) 0,03716:00 0,73 (0,7-0,76) <0,001 0,73 (0,7-0,77) <0,001 0,87 (0,79-0,95) 0,99317:00 0,71 (0,68-0,74) <0,001 0,72 (0,68-0,76) <0,001 0,89 (0,81-0,97) 0,99318:00 0,8 (0,76-0,83) <0,001 0,81 (0,77-0,85) <0,001 0,91 (0,83-1) 0,99319:00 0,76 (0,73-0,8) <0,001 0,76 (0,73-0,8) <0,001 0,95 (0,87-1,04) 0,99320:00 0,92 (0,88-0,96) 0,014 0,92 (0,88-0,96) 0,049 0,97 (0,89-1,06) 0,99321:00 0,86 (0,83-0,9) <0,001 0,87 (0,83-0,91) <0,001 0,96 (0,88-1,05) 0,99322:00 0,93 (0,89-0,97) 0,095 0,92 (0,88-0,96) 0,108 1,01 (0,93-1,1) 0,993

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Confidential: For Review Only23:00 0,94 (0,9-0,97) 0,363 0,94 (0,9-0,98) 0,998 1 (0,92-1,1) 0,993

No Aspirin 1 1 1

01:00 0,9 (0,86-0,94) <0,001 0,88 (0,83-0,92) <0,001 0,99 (0,93-1,06) 0,99302:00 0,94 (0,9-0,98) 0,480 0,91 (0,87-0,96) 0,067 1,02 (0,96-1,09) 0,99303:00 0,94 (0,9-0,97) 0,416 0,9 (0,85-0,94) 0,010 1,03 (0,96-1,09) 0,99304:00 0,91 (0,87-0,95) 0,001 0,89 (0,85-0,94) 0,004 1,01 (0,95-1,08) 0,99305:00 0,88 (0,85-0,92) <0,001 0,84 (0,8-0,89) <0,001 1,01 (0,95-1,07) 0,99306:00 1,01 (0,97-1,05) 1,000 0,95 (0,9-0,99) 0,998 1,05 (0,99-1,12) 0,99307:00 1,18 (1,14-1,22) <0,001 1,1 (1,05-1,15) 0,040 1,11 (1,05-1,18) 0,23408:00 1,74 (1,69-1,8) <0,001 1,59 (1,53-1,66) <0,001 1,31 (1,24-1,38) <0,00109:00 1,37 (1,33-1,42) <0,001 1,23 (1,17-1,28) <0,001 1,26 (1,2-1,33) <0,00110:00 1,49 (1,44-1,54) <0,001 1,31 (1,25-1,37) <0,001 1,32 (1,25-1,39) <0,00111:00 1,24 (1,19-1,28) <0,001 1,11 (1,06-1,16) 0,010 1,26 (1,19-1,33) <0,00112:00 1,47 (1,42-1,53) <0,001 1,37 (1,31-1,43) <0,001 1,28 (1,21-1,35) <0,00113:00 1,12 (1,08-1,17) <0,001 1,03 (0,98-1,09) 0,998 1,18 (1,11-1,25) <0,00114:00 1,16 (1,12-1,21) <0,001 1,07 (1,02-1,13) 0,998 1,18 (1,12-1,25) <0,00115:00 1,21 (1,17-1,26) <0,001 1,14 (1,09-1,2) <0,001 1,21 (1,14-1,28) <0,00116:00 1,07 (1,03-1,11) 0,141 1,03 (0,98-1,08) 0,998 1,14 (1,07-1,21) 0,02017:00 0,98 (0,94-1,02) 1,000 0,96 (0,91-1,01) 0,998 1,06 (0,99-1,12) 0,99318:00 0,98 (0,94-1,02) 1,000 0,94 (0,89-0,99) 0,998 1,07 (1,01-1,14) 0,99319:00 0,95 (0,91-0,99) 1,000 0,94 (0,89-0,98) 0,998 1,03 (0,96-1,09) 0,99320:00 1,03 (0,99-1,07) 1,000 1,01 (0,97-1,06) 0,998 1,04 (0,98-1,1) 0,99321:00 0,92 (0,88-0,95) 0,006 0,89 (0,85-0,94) 0,002 1 (0,94-1,07) 0,99322:00 0,96 (0,93-1) 1,000 0,94 (0,89-0,98) 0,998 1,01 (0,95-1,07) 0,99323:00 0,93 (0,9-0,97) 0,156 0,89 (0,85-0,93) 0,002 1,02 (0,96-1,08) 0,993

ACE-I/ARB 1 1 1

01:00 0,87 (0,83-0,91) <0,001 0,9 (0,85-0,95) 0,026 0,9 (0,81-1,01) 0,99302:00 0,87 (0,83-0,92) <0,001 0,89 (0,84-0,94) 0,009 0,93 (0,84-1,03) 0,99303:00 0,87 (0,83-0,91) <0,001 0,89 (0,84-0,94) 0,011 0,89 (0,8-0,99) 0,99304:00 0,81 (0,77-0,85) <0,001 0,84 (0,79-0,88) <0,001 0,92 (0,83-1,02) 0,99305:00 0,78 (0,75-0,82) <0,001 0,82 (0,77-0,86) <0,001 0,9 (0,81-1) 0,99306:00 0,84 (0,8-0,88) <0,001 0,83 (0,79-0,88) <0,001 0,91 (0,83-1,01) 0,99307:00 1,03 (0,98-1,08) 1,000 0,99 (0,94-1,05) 0,998 1,02 (0,93-1,13) 0,99308:00 1,48 (1,42-1,55) <0,001 1,37 (1,31-1,43) <0,001 1,16 (1,06-1,27) 0,83909:00 1,01 (0,96-1,05) 1,000 0,94 (0,89-0,98) 0,998 1,07 (0,97-1,17) 0,99310:00 1,03 (0,98-1,08) 1,000 0,94 (0,89-0,99) 0,998 1,06 (0,97-1,16) 0,99311:00 0,79 (0,75-0,83) <0,001 0,75 (0,71-0,8) <0,001 0,97 (0,88-1,07) 0,99312:00 1,04 (0,99-1,08) 1,000 0,97 (0,92-1,02) 0,998 1,03 (0,94-1,13) 0,99313:00 0,74 (0,7-0,78) <0,001 0,73 (0,69-0,77) <0,001 0,9 (0,81-0,99) 0,99314:00 0,78 (0,74-0,82) <0,001 0,76 (0,72-0,81) <0,001 0,92 (0,83-1,01) 0,99315:00 0,82 (0,78-0,86) <0,001 0,81 (0,76-0,85) <0,001 0,9 (0,81-0,99) 0,99316:00 0,74 (0,7-0,78) <0,001 0,75 (0,7-0,79) <0,001 0,85 (0,77-0,94) 0,99317:00 0,72 (0,68-0,76) <0,001 0,73 (0,69-0,77) <0,001 0,9 (0,81-0,99) 0,99318:00 0,78 (0,74-0,82) <0,001 0,8 (0,75-0,84) <0,001 0,87 (0,78-0,97) 0,99319:00 0,77 (0,74-0,81) <0,001 0,79 (0,74-0,83) <0,001 0,91 (0,82-1,01) 0,99320:00 0,93 (0,88-0,97) 0,484 0,93 (0,89-0,98) 0,998 0,94 (0,84-1,04) 0,993

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Confidential: For Review Only21:00 0,83 (0,79-0,87) <0,001 0,83 (0,78-0,87) <0,001 0,94 (0,85-1,05) 0,99322:00 0,91 (0,86-0,95) 0,016 0,93 (0,88-0,98) 0,998 0,87 (0,78-0,97) 0,99323:00 0,92 (0,88-0,96) 0,141 0,94 (0,89-0,99) 0,998 0,93 (0,84-1,04) 0,993

No ACE-I/ARB 1 1 1

01:00 0,89 (0,86-0,93) <0,001 0,87 (0,83-0,91) <0,001 1,01 (0,95-1,07) 0,99302:00 0,94 (0,91-0,97) 0,111 0,91 (0,87-0,95) 0,007 1,04 (0,98-1,1) 0,99303:00 0,93 (0,9-0,96) 0,021 0,88 (0,85-0,92) <0,001 1,06 (1-1,12) 0,99304:00 0,89 (0,86-0,92) <0,001 0,87 (0,83-0,9) <0,001 1,02 (0,96-1,08) 0,99305:00 0,85 (0,82-0,88) <0,001 0,81 (0,77-0,85) <0,001 1,02 (0,96-1,08) 0,99306:00 1 (0,97-1,04) 1,000 0,95 (0,91-0,99) 0,998 1,08 (1,02-1,14) 0,99307:00 1,13 (1,09-1,17) <0,001 1,03 (0,99-1,07) 0,998 1,13 (1,07-1,2) 0,00508:00 1,64 (1,59-1,69) <0,001 1,45 (1,4-1,51) <0,001 1,32 (1,25-1,38) <0,00109:00 1,26 (1,22-1,3) <0,001 1,11 (1,07-1,15) <0,001 1,22 (1,16-1,29) <0,00110:00 1,35 (1,31-1,4) <0,001 1,17 (1,12-1,21) <0,001 1,28 (1,22-1,35) <0,00111:00 1,11 (1,07-1,15) <0,001 0,98 (0,94-1,02) 0,998 1,21 (1,14-1,27) <0,00112:00 1,33 (1,29-1,37) <0,001 1,21 (1,16-1,25) <0,001 1,23 (1,17-1,3) <0,00113:00 1,01 (0,97-1,04) 1,000 0,92 (0,88-0,96) 0,102 1,12 (1,06-1,18) 0,05014:00 1,06 (1,02-1,09) 0,342 0,97 (0,93-1,01) 0,998 1,13 (1,07-1,2) 0,00615:00 1,1 (1,06-1,13) <0,001 1,02 (0,98-1,06) 0,998 1,14 (1,08-1,21) 0,00116:00 1 (0,96-1,03) 1,000 0,94 (0,9-0,99) 0,998 1,11 (1,05-1,18) 0,17917:00 0,92 (0,89-0,95) 0,001 0,89 (0,85-0,93) <0,001 1,04 (0,98-1,1) 0,99318:00 0,95 (0,92-0,98) 0,989 0,92 (0,88-0,96) 0,025 1,07 (1,01-1,13) 0,99319:00 0,9 (0,87-0,94) <0,001 0,88 (0,84-0,92) <0,001 1,03 (0,97-1,09) 0,99320:00 1 (0,97-1,04) 1,000 0,98 (0,94-1,02) 0,998 1,04 (0,98-1,1) 0,99321:00 0,92 (0,89-0,96) 0,003 0,91 (0,87-0,95) 0,005 1,01 (0,95-1,07) 0,99322:00 0,97 (0,94-1) 1,000 0,93 (0,89-0,97) 0,211 1,05 (0,99-1,12) 0,99323:00 0,94 (0,91-0,98) 0,276 0,91 (0,87-0,95) 0,003 1,04 (0,98-1,1) 0,993

Statins 1 1 1

01:00 0,85 (0,81-0,9) <0,001 0,86 (0,81-0,91) <0,001 0,95 (0,84-1,06) 0,99302:00 0,86 (0,82-0,91) <0,001 0,88 (0,84-0,94) 0,010 0,91 (0,81-1,02) 0,99303:00 0,84 (0,79-0,88) <0,001 0,84 (0,79-0,89) <0,001 0,94 (0,84-1,06) 0,99304:00 0,8 (0,75-0,84) <0,001 0,81 (0,76-0,86) <0,001 0,95 (0,84-1,07) 0,99305:00 0,74 (0,7-0,78) <0,001 0,76 (0,72-0,81) <0,001 0,88 (0,78-0,99) 0,99306:00 0,84 (0,8-0,89) <0,001 0,84 (0,79-0,89) <0,001 0,93 (0,83-1,05) 0,99307:00 0,98 (0,93-1,03) 1,000 0,93 (0,88-0,98) 0,998 1,06 (0,95-1,18) 0,99308:00 1,45 (1,39-1,52) <0,001 1,33 (1,27-1,4) <0,001 1,17 (1,05-1,29) 0,99309:00 1 (0,96-1,05) 1,000 0,95 (0,9-1) 0,998 1,05 (0,95-1,17) 0,99310:00 1,04 (0,99-1,09) 1,000 0,94 (0,89-0,99) 0,998 1,13 (1,02-1,26) 0,99311:00 0,81 (0,77-0,85) <0,001 0,77 (0,73-0,82) <0,001 1,03 (0,92-1,14) 0,99312:00 1 (0,95-1,05) 1,000 0,94 (0,89-0,99) 0,998 1,02 (0,92-1,13) 0,99313:00 0,74 (0,7-0,78) <0,001 0,74 (0,7-0,79) <0,001 0,9 (0,8-1) 0,99314:00 0,78 (0,74-0,82) <0,001 0,74 (0,7-0,79) <0,001 0,98 (0,88-1,09) 0,99315:00 0,8 (0,76-0,84) <0,001 0,79 (0,75-0,84) <0,001 0,85 (0,76-0,96) 0,99316:00 0,73 (0,69-0,77) <0,001 0,74 (0,7-0,79) <0,001 0,85 (0,76-0,95) 0,99317:00 0,73 (0,69-0,77) <0,001 0,73 (0,68-0,77) <0,001 0,96 (0,86-1,08) 0,99318:00 0,77 (0,73-0,81) <0,001 0,78 (0,74-0,83) <0,001 0,89 (0,79-1) 0,993

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Supplementary table 2. Subgroup analyses.

All p-values are adjusted for multiple testing.

ACE-I= Angiotensin Converting Enzyme-Inhibitors: ARB= angiotensin receptor blocker;

CAD=Coronary artery disease.

19:00 0,77 (0,73-0,81) <0,001 0,79 (0,74-0,83) <0,001 0,91 (0,81-1,02) 0,99320:00 0,92 (0,87-0,96) 0,253 0,92 (0,87-0,98) 0,998 0,93 (0,83-1,05) 0,99321:00 0,84 (0,8-0,88) <0,001 0,85 (0,8-0,9) <0,001 0,91 (0,81-1,02) 0,99322:00 0,91 (0,87-0,96) 0,095 0,92 (0,87-0,97) 0,743 0,94 (0,84-1,05) 0,99323:00 0,94 (0,89-0,98) 1,000 0,95 (0,9-1,01) 0,998 0,97 (0,87-1,09) 0,993

No Statins 1 1 1

01:00 0,9 (0,87-0,93) <0,001 0,89 (0,85-0,93) <0,001 0,99 (0,94-1,05) 0,99302:00 0,94 (0,91-0,97) 0,073 0,91 (0,88-0,95) 0,005 1,04 (0,98-1,1) 0,99303:00 0,94 (0,91-0,97) 0,165 0,91 (0,88-0,95) 0,007 1,03 (0,98-1,09) 0,99304:00 0,89 (0,86-0,92) <0,001 0,88 (0,84-0,91) <0,001 1,01 (0,95-1,07) 0,99305:00 0,87 (0,84-0,9) <0,001 0,84 (0,8-0,87) <0,001 1,02 (0,96-1,08) 0,99306:00 0,99 (0,96-1,02) 1,000 0,94 (0,9-0,97) 0,458 1,07 (1,01-1,13) 0,99307:00 1,14 (1,11-1,18) <0,001 1,06 (1,02-1,1) 0,998 1,12 (1,06-1,18) 0,02508:00 1,64 (1,6-1,69) <0,001 1,47 (1,42-1,52) <0,001 1,31 (1,24-1,37) <0,00109:00 1,24 (1,21-1,28) <0,001 1,09 (1,05-1,13) 0,005 1,22 (1,16-1,28) <0,00110:00 1,33 (1,29-1,37) <0,001 1,15 (1,11-1,19) <0,001 1,25 (1,19-1,31) <0,00111:00 1,08 (1,05-1,12) 0,001 0,96 (0,92-1) 0,998 1,18 (1,12-1,24) <0,00112:00 1,33 (1,29-1,37) <0,001 1,21 (1,16-1,25) <0,001 1,22 (1,16-1,28) <0,00113:00 0,99 (0,96-1,02) 1,000 0,9 (0,86-0,94) 0,001 1,1 (1,05-1,17) 0,18814:00 1,04 (1,01-1,08) 1,000 0,97 (0,93-1,01) 0,998 1,1 (1,05-1,16) 0,20515:00 1,09 (1,05-1,12) <0,001 1,01 (0,97-1,05) 0,998 1,14 (1,08-1,2) 0,00116:00 0,98 (0,95-1,01) 1,000 0,93 (0,89-0,97) 0,267 1,1 (1,04-1,16) 0,76117:00 0,9 (0,87-0,93) <0,001 0,88 (0,84-0,92) <0,001 1,01 (0,96-1,07) 0,99318:00 0,94 (0,91-0,97) 0,174 0,91 (0,88-0,95) 0,009 1,05 (1-1,11) 0,99319:00 0,9 (0,87-0,93) <0,001 0,87 (0,84-0,91) <0,001 1,02 (0,97-1,08) 0,99320:00 1 (0,97-1,04) 1,000 0,98 (0,94-1,02) 0,998 1,03 (0,98-1,09) 0,99321:00 0,91 (0,88-0,94) <0,001 0,89 (0,85-0,93) <0,001 1,01 (0,95-1,07) 0,99322:00 0,96 (0,93-0,99) 1,000 0,94 (0,9-0,97) 0,384 1,03 (0,97-1,08) 0,99323:00 0,93 (0,9-0,96) 0,019 0,9 (0,86-0,94) <0,001 1,02 (0,97-1,08) 0,993

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Shown are the associated risks overall MI in various subgroups and major national

holidays expressed as incidence rate ratios. Christmas/New years include Christmas

Eve, Christmas Day, Boxing Day, New Years Eve and Day as well as the epiphany.

Easter holiday includes Good Friday, Easter Eve and Day and Easter Monday. P-

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Confidential: For Review Onlyvalue<0.05 for all bars not crossing the red line. P-values after adjustment for



Left figure shows the associated risk of holidays on MI requiring revascularization

after coronary angiography was performed vs. those who did not undergo

PCI/CABG. Right figure shows the associated risk of MI on Christmas/New Years’

holiday for each age quartile. Christmas/New Years’ include Christmas Eve,

Christmas Day, Boxing Day, New Years’ Eve and Day as well as the epiphany. P-

value<0.05 for all bars not crossing the red line.

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Confidential: For Review OnlySuppementary Figure 3. Subgroup analyses of day of week.

Shown are the associated risks overall MI in various subgroups and day of week

expressed as incidence rate ratio. Reference period for day of week is Sunday and

reference hour for hour of symptom onset is 00:00. P-values after adjustment for


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Confidential: For Review OnlySuppementary Figure 4. Subgroup analyses of hour of symptom onset

Shown are the associated risks overall MI in various subgroups and hour of

symptom onset expressed as incidence rate ratios. Reference period is 00:00. P-

values after adjustment for multiple testing are presented in Supplementary Table

2.

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Confidential: For Review Only - BMJ...Moman A.Mohammad1, Sofia Karlsson1, Jonathan Haddad1, Björn...

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