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Department of Surgery, University of Toronto, Toronto, ON, M5S 1A1, CanadaKeenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, ON, M5B 1W8, Canada
Population Health Research Institute, McMaster University, Hamilton, Ontario, CanadaDepartment of Medicine, McMaster University, Hamilton, Ontario, CanadaDepartment of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
Population Health Research Institute, McMaster University, Hamilton, Ontario, CanadaSchool of Rehabilitation Sciences, McMaster University, Hamilton, ON, Canada
Population Health Research Institute, McMaster University, Hamilton, Ontario, CanadaDepartment of Medicine, McMaster University, Hamilton, Ontario, Canada
Population Health Research Institute, McMaster University, Hamilton, Ontario, CanadaDepartment of Medicine, McMaster University, Hamilton, Ontario, CanadaDepartment of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
No significant differences in cardiovascular outcomes were observed in COMPASS trial patients with a systolic IAD>15 mmHg or IAD<15 mmHg
•
What Is Relevant?:
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Unlike other patient populations, measuring IAD for risk stratification purposes does not appear to be useful in patients with established vascular disease.
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Summary - of the conclusions of the study.
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Patients with an IAD≥15 mmHg were at a similar risk of cardiovascular outcomes compared to patients with an IAD<15 mmHg – with the exception of stroke.
Abstract
Background and aims
Systolic blood pressure interarm difference (IAD) predicts cardiovascular morbidity and mortality in primary prevention populations. We examined the predictive value of IAD and the effects of treatment with the combination of rivaroxaban 2.5 mg twice daily plus aspirin 100 mg once daily versus aspirin 100 mg once daily according to IAD in patients with chronic coronary artery disease or peripheral artery disease.
Methods
COMPASS trial patients with IAD <15 mmHg and IAD >15 mmHg were compared with respect to thirty-month incidence risk of: 1) composite of stroke, myocardial infarction, or cardiovascular death (MACE), 2) composite of acute limb-ischemia or vascular amputation (MALE), 3) composite of MACE or MALE, and 4) effects of treatment with the combination versus aspirin alone on these outcomes.
Results
24,539 patients had an IAD<15 mmHg and 2,776 had an IAD ≥15 mm Hg. Relative to patients with IAD ≥15 mm Hg, those with IAD<15 mmHg had similar incidence rates for all measured outcomes including the composite of MACE or MALE (HR 1.12 [95% CI: 0.95 to 1.31], p = 0.19), with the exception of stroke (HR 1.38 [95% CI: 1.02 to 1.88], p = 0.04). Compared to aspirin alone, the combination consistently reduced the composite of MACE or MALE in both IAD <15 mmHg (HR 0.74 [95% CI: 0.65–0.85], p < 0.0001, ARR = −23.1) and IAD>15 mmHg (HR 0.65 [95% CI: 0.44–0.96], p = 0.03; ARR = −32.6, p interaction = 0.53) groups.
Conclusions
Unlike primary prevention populations, measuring IAD for risk stratification purposes does not appear to be useful in patients with established vascular disease.
Disability-adjusted life years (dalys) for 291 diseases and injuries in 21 regions, 1990–2010: a systematic analysis for the global burden of disease study 2010.
Age-and sex-specific burden of cardiovascular disease attributable to 5 major and modifiable risk factors in 10 asian countries of the western pacific region.
Global, regional, and national age-sex specific mortality for 264 causes of death, 1980–2016: a systematic analysis for the global burden of disease study 2016.
]. Hypertension is a major modifiable risk factor for cardiovascular disease. Achieving a small reduction in blood pressure (BP) can significantly reduce the risk of cardiovascular-related events, morbidity, and mortality [
]. BP measurements can be readily obtained in primary care settings.
Guidelines for the management of hypertension recommend measuring BP in both arms, with the higher-pressure value given preference for subsequent measurements [
acc/aha/aapa/abc/acpm/ags/apha/ash/aspc/nma/pcna guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the american college of cardiology/american heart association task force on clinical practice guidelines.
esh/esc practice guidelines for the management of arterial hypertension: Esh-esc the task force for the management of arterial hypertension of the european society of hypertension (esh) and of the european society of cardiology (esc).
]. Systolic interarm difference (IAD), defined as the difference in blood pressure readings between the upper extremities, is present in 3.6% of patients in primary care and is reported to be present in a higher proportion of patients with PAD, chronic kidney disease, or diabetes [
Association of an inter-arm systolic blood pressure difference with all-cause and cardiovascular mortality: an updated meta-analysis of cohort studies.
], but it is unclear whether preventive intervention would improve patient outcome.
In the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial, we demonstrated that dual pathway therapy regimen with rivaroxaban 2.5 mg twice daily plus aspirin, compared to aspirin alone, reduced major adverse cardiovascular events (MACE), major adverse limb events (MALE) and mortality in patients with chronic CAD or PAD [
]. In this investigation, we sought to assess the predictive value of interarm BP differences in patients enrolled in the COMPASS trial and the effects of treatment according to IAD blood pressure differences.
2. Patients and methods
2.1 Patient population and demographics
The study design and findings of the COMPASS trial have previously been published [
]. In summary, the COMPASS trial was a randomized, multicentre, placebo-controlled trial of 27,395 patients with chronic coronary artery disease (CAD) or peripheral arterial disease (PAD) comparing the combination of rivaroxaban 2.5 mg twice daily and aspirin 100 mg (dual pathway antithrombotic regimen) or rivaroxaban 5 mg twice daily with aspirin 100 mg once daily for the prevention of MACE, MALE and mortality. The trial was halted early after a mean follow-up of 23 months due to the clear benefit observed with rivaroxaban 2.5 mg twice daily plus aspirin over aspirin alone. Participants in the COMPASS trial randomized to the combination of rivaroxaban and aspirin or to aspirin alone were included in this analysis.
2.2 Systolic interarm blood pressure assessment
Upon enrolment in the COMPASS trial, patients’ systolic blood pressures were measured in both arms by trained study personnel following 5 min of rest. Our primary analysis was based on a systolic IAD of ≥15 mmHg between the right and left arm as previous studies have suggested increased specificity for arterial stenosis with an IAD cutoff of 15 mmHg as opposed to an IAD cutoff of 10 mm Hg [
]. The primary outcome was major adverse cardiovascular events (MACE), defined as the composite of cardiovascular death, myocardial infarction or ischemic stroke. Secondary efficacy outcomes included major adverse limb events (MALE), defined as the composite of acute or chronic limb ischemia limb ischemia leading to an intervention or major vascular amputation. Main safety outcome was major bleeding, defined according to a modification of the International Society on Thrombosis and Haemostasis (ISTH) criteria. This included fatal bleeding, symptomatic bleeding into a critical organ, bleeding into a surgical site requiring reoperation, and bleeding that led to hospitalization (included presentation to an acute care facility).
2.4 Statistical analysis
Data and analysis for this study was obtained from the 27,395 patients who were enrolled in the COMPASS trial. Of these, 80 patients were excluded as their IAD was not assessed. All analyses were conducted in the intention-to-treat study population and all clinical events that occurred between randomization and the end of observation date were included in the analysis. Baseline characteristics were presented as means with standard deviation for continuous variables and frequencies with percentages for categorical variables. Hazard ratios (HR) and 95% confidence intervals (CIs) were reported for the time to event analysis of the primary outcomes and derived from a Cox Proportional hazard model in the overall population. Event rates were estimated as the number of first events per 100 person-years of outcome specific follow-up (i.e. time from randomization until either the first occurrence of the outcome or the last follow-up with no outcome), and 30-month Kaplan-Meier incidence risk was reported for all main outcomes. Subgroup analyses were conducted among patients with CAD and PAD, as well as for event rates according to categories of baseline risk of cardiovascular disease. All tests were two-sided, with a p-value <0.05 considered to be significant. Analyses were conducted using SAS version 9.4 (SAS Institute).
3. Results
3.1 Baseline characteristics
From the overall COMPASS population, a total of 24,539 patients had an IAD<15 mmHg with an average age 68.2 ± 8.0 years. Females accounted for 21.9% of the patients within this group. The remaining 2,776 patients had an IAD ≥15 mmHg (mean age 68.8 ± 8.0 years; 22.3% females). Baseline characteristics of patients within each IAD group are shown in Table 1 (corresponding data for the entire COMPASS population are presented in Supplementary Table S1). The IAD was normally distributed among the recruited patients (Supplementary Fig. 1) Patients in the IAD ≥15 mmHg group had significantly higher body-mass index (28.9 ± 4.9 vs 28.3 ± 4.7 kg/m2), systolic blood pressure (139 ± 18 vs 135 ± 17 mm Hg), and former tobacco use (51.0% vs 46.1%) compared to those with IAD<15 mm Hg. The prevalence of PAD was higher in the IAD ≥15 mmHg group, but CAD, myocardial infarction, and heart failure, were more common among patients with IAD<15 mm Hg. Lastly, patients in IAD ≥15 mmHg were more often treated with angiotensin-converting enzyme inhibitor or angiotensin receptor blocker (72.7% vs 71.1%), calcium-channel blocker (28.1% vs 26.4%), diuretic (32.2% vs 29.4%), and nonsteroidal anti-inflammatory drugs (6.3% vs 5.2%) compared to patients with IAD<15 mmHg (Table 1).
Table 1Baseline characteristics of patients by IAD15.
IAD <15 mmHg(N = 24539)
IAD ≥15 mmHg(N = 2776)
p value
Age (yr)
68.2 ± 8.0
68.8 ± 7.4
<0.0001
Female sex
5366 (21.9)
618 (22.3)
0.63
Body-mass index (kg/m2)
28.3 ± 4.7
28.9 ± 4.9
<0.0001
Systolic blood pressure (mmHg)
135 ± 17
139 ± 18
<0.0001
Diastolic blood pressure (mmHg)
78 ± 10
78 ± 11
0.12
Total cholesterol (mmol/l)
4.2 ± 1.1
4.1 ± 1.1
0.001
Tobacco use
Never
7935 (32.3)
796 (28.7)
<0.0001
Former
11319 (46.1)
1415 (51.0)
<0.0001
Current
5285 (21.5)
565 (20.4)
0.15
Hypertension
18501 (75.4)
2071 (74.6)
0.36
Diabetes
9276 (37.8)
1035 (37.3)
0.59
Previous stroke
925 (3.8)
102 (3.7)
0.80
Previous myocardial infarction
15359 (62.6)
1637 (59.0)
0.0002
Heart failure
5423 (22.1)
461 (16.6)
<0.0001
Coronary artery disease
22281 (90.8)
2471 (89.0)
0.002
Peripheral arterial disease
6541 (26.7)
907 (32.7)
<0.0001
Estimated GFR
<30 ml/min
215 (0.9)
27 (1.0)
0.61
30 to <60 ml/min
5405 (22.0)
610 (22.0)
0.94
≥60 ml/min
18911 (77.1)
2139 (77.1)
0.97
Race
White
15081 (61.5)
1889 (68.0)
<0.0001
Black
223 (0.9)
36 (1.3)
0.05
Asian
3936 (16.0)
324 (11.7)
<0.0001
Other
5299 (21.6)
527 (19.0)
0.001
Geographic region
North America
3349 (13.6)
535 (19.3)
<0.0001
South America
5629 (22.9)
508 (18.3)
<0.0001
Western Europe, Israel, Australia, or South Africa
7398 (30.1)
1127 (40.6)
<0.0001
Eastern Europe
4498 (18.3)
324 (11.7)
<0.0001
Asia-Pacific
3665 (14.9)
282 (10.2)
<0.0001
Medication
ACE inhibitor or ARB
17450 (71.1)
2019 (72.7)
0.07
Calcium-channel blocker
6469 (26.4)
779 (28.1)
0.05
Diuretic
7208 (29.4)
893 (32.2)
0.002
Beta blocker
17252 (70.3)
1870 (67.4)
0.001
Lipid-lowering agent
22028 (89.8)
2497 (89.9)
0.76
NSAID
1281 (5.2)
175 (6.3)
0.02
Non-study PPI
8715 (35.5)
1038 (37.4)
0.05
For continuous variables, plus-minus values are mean ± standard deviation. For categorical variables, frequency (percent) are shown.
p value is from the Wilcoxon 2-sample test for continuous variables, and Pearson chi-square test for categorical variables.
The incidence rate for the primary efficacy and safety outcomes of the COMPASS trial in patients randomized to receive the dual pathway antithrombotic regimen or aspirin alone are shown in Table 2. Our data revealed consistent patterns of lower outcome incident rates in patients with IAD <15 mmHg versus those with IAD ≥15 mm Hg, but none of these differences were statistically significant except for stroke (higher in IAD ≥15 mmHg patients with a hazard ratio (HR) of 1.38 (95% CI: 1.02 to 1.88; p-value: 0.04)). Hazard ratios of MACE and MALE were noted to be HR 1.13 (95% CI: 0.95 to 1.34; p-value: 0.16) and 1.05 (95% CI: 0.61 to 1.79; p-value: 0.86), respectively.
Table 2Study outcomes in IAD <15 mmHg and IAD >15 mmHg patients with chronic coronary or peripheral artery disease.
IAD <15 mmHg(N = 24539)
IAD ≥15 mmHg(N = 2776)
IAD ≥15 mmHg vs.IAD <15 mmHg
No. of first events (%)
Annual rate, %/yr
No. of first events (%)
Annual rate, %/yr
Hazard Ratio(95% CI)
Cardiovascular death, stroke, or myocardial infarction (MACE)
1166 (4.8)
2.5
152 (5.5)
2.8
1.13 (0.95–1.34)
Cardiovascular death
491 (2.0)
1.0
65 (2.3)
1.2
1.14 (0.88–1.48)
Stroke
295 (1.2)
0.6
47 (1.7)
0.9
1.38 (1.02–1.88)
Myocardial infarction
504 (2.1)
1.1
57 (2.1)
1.1
0.98 (0.74–1.29)
Major adverse limb event (MALE)
124 (0.5)
0.3
15 (0.5)
0.3
1.05 (0.61–1.79)
Acute limb ischemia (ALI)
79 (0.3)
0.2
7 (0.3)
0.1
0.77 (0.35–1.66)
Chronic limb ischemia (CLI)
55 (0.2)
0.1
8 (0.3)
0.1
1.26 (0.60–2.65)
MACE or MALE
1281 (5.2)
2.8
165 (5.9)
3.1
1.12 (0.95–1.31)
Death from any cause
934 (3.8)
2.0
120 (4.3)
2.2
1.10 (0.91–1.34)
Major bleeding
636 (2.6)
1.4
74 (2.7)
1.4
1.01 (0.79–1.28)
Minor bleeding
1860 (7.6)
4.2
215 (7.7)
4.2
1.01 (0.88–1.16)
Any bleeding
2391 (9.7)
5.5
277 (10.0)
5.5
1.01 (0.89–1.14)
Percent (%) is the proportion of patients with an outcome. Percent per year (%/yr) is the rate per 100 patient-years of follow-up.
Hazard ratios (95% CI) and p values are from the univariate Cox proportional hazards regression models.
Efficacy outcomes of patients randomized to receive the dual pathway antithrombotic regimen compared to aspirin alone are presented in Table 3. The combination of rivaroxaban 2.5 mg and aspirin relative to aspirin alone reduced a composite of MACE or MALE events in both the IAD <15 mmHg group (HR 0.74 [95% CI: 0.65–0.85]) and the IAD ≥15 mmHg group (HR 0.65 [95% CI: 0.44–0.96, p [interaction] = 0.53, Table 3 and Supplementary Fig. 2). Similar patterns were observed for MACE group (IAD ≥15 mm Hg: HR 0.69 [95% CI: 0.46–1.03]; IAD <15 mm Hg: HR 0.76 [95% CI: 0.66–0.87], p [interaction] = 0.67) and MALE (IAD ≥15 mm Hg: HR 0.23 [95% CI: 0.05–1.1], IAD <15 mm Hg: HR 0.57 [95% CI: 0.37–0.88], p [interaction] = 0.29) (Table 3, Fig. 1).
Table 3Effects of dual pathway COMPASS compared with aspirin alone on the efficacy outcome in patients with IAD <15 mmHg and IAD >15 mmHg
Based on Kaplan-Meier estimates of cumulative risk at 30 months.
, at 30 months
No. of first events/patients (%)
Annual rate, %/yr
No. of first events/patients (%)
Annual rate, %/yr
Hazard Ratio (95% CI)
p value
p value for interaction
Cardiovascular death, stroke, or myocardial infarction (MACE)
0.67
IAD <15 mmHg
335/8168 (4.1)
2.2
440/8189 (5.4)
2.9
0.76 (0.66–0.87)
0.0001
−20.1
50
IAD ≥15 mmHg
41/954 (4.3)
2.2
56/911 (6.1)
3.2
0.69 (0.46–1.03)
0.07
−26.9
38
Major adverse limb event (MALE)
0.29
IAD <15 mm Hg
32/8168 (0.4)
0.2
56/8189 (0.7)
0.4
0.57 (0.37–0.88)
0.01
−3.7
267
IAD ≥15 mmHg
2/954 (0.2)
0.1
8/911 (0.9)
0.5
0.23 (0.05–1.10)
0.05
−9.5
105
MACE or MALE
0.53
IAD <15 mmHg
365/8168 (4.5)
2.4
489/8189 (6.0)
3.2
0.74 (0.65–0.85)
<0.0001
−23.1
44
IAD ≥15 mmHg
43/954 (4.5)
2.3
62/911 (6.8)
3.6
0.65 (0.44–0.96)
0.03
−32.6
31
Percent (%) is the proportion of patients with an outcome. Percent per year (%/yr) is the rate per 100 patient-years of follow-up.
Hazard ratios (95% CI) are from the stratified Cox proportional hazards regression models fit in the respective subgroup. p values are from the stratified log-rank tests.
a Based on Kaplan-Meier estimates of cumulative risk at 30 months.
The safety outcomes in patients with IAD <15 mmHg and IAD ≥15 mmHg randomized to receive dual pathway antithrombotic regimen compared with aspirin are summarized displayed in Table 4. Compared to patients on monotherapy aspirin, those on the dual pathway antithrombotic regimen similar increase in bleeding risk irrespective of IAD group (IAD <15 mm Hg: HR 1.73, [95% CI: 1.41–2.11]; IAD ≥15 mm Hg: HR 1.51, [95% CI: 0.85–2.67], p [interaction] = 0.68). Thus, despite consistent treatment effects, no significant differences were observed when comparing patients with IAD <15 mmHg and IAD ≥15 mm Hg.
Table 4Safety outcomes of dual pathway COMPASS compared with aspirin alone on the efficacy outcome in patients with IAD <15 mmHg and IAD >15 mmHg
Based on Kaplan-Meier estimates of cumulative risk at 30 months.
, at 30 months
No. of first events/patients (%)
Annual rate, %/yr
No. of first events/patients (%)
Annual rate, %/yr
Hazard Ratio (95% CI)
p value
p value for interaction
Major bleeding
0.68
IAD <15 mmHg
257/8168 (3.1)
1.7
150/8189 (1.8)
1.0
1.73 (1.41–2.11)
<0.0001
16.3
−62
IAD ≥15 mmHg
30/954 (3.1)
1.6
19/911 (2.1)
1.1
1.51 (0.85–2.67)
0.16
5.3
−188
Percent (%) is the proportion of patients with an outcome. Percent per year (%/yr) is the rate per 100 patient-years of follow-up.
Hazard ratios (95% CI) are from the stratified Cox proportional hazards regression models fit in the respective subgroup. p values are from the stratified log-rank tests.
a Based on Kaplan-Meier estimates of cumulative risk at 30 months.
3.4 Subgroup analysis in patients with peripheral and coronary arterial disease
Among patients with PAD, those with IAD <15 mmHg compared to patients with IAD ≥15 mmHg had similar incidence rates for all measured outcomes except stroke (higher in IAD ≥15 mmHg patients) (Supplementary Table 1). Among patients with CAD there were no significant differences for any outcome according to IAD (Supplementary Table 2).
With regards to the effect of antithrombotic therapies, among patients with CAD only, MACE outcomes, as well as MACE or MALE events were non-significantly reduced in IAD <15 mmHg patients randomized to dual pathway COMPASS compared to aspirin alone (Supplementary Table 3).
In terms of the primary safety outcome, major bleeding was similar in IAD <15 mmHg patients compared to patients with IAD >15 mmHg for both PAD and CAD patients (Supplementary Tables 3 and 4).
3.5 Subgroup analysis according to baseline risk of cardiovascular disease
Exploratory subgroup analysis was also conducted to assess event rates in patients with IAD <15 mmHg compared to patients with IAD ≥15 mmHg according to baseline risk of cardiovascular disease. Based on these data, IAD may predict outcomes in patients with less advanced disease severity, but not in patients with an advanced disease state (Supplementary Table 5).
4. Discussion
In this study, patients from the COMPASS trial with a systolic IAD ≥15 mmHg and IAD<15 mmHg were compared. Our data suggests that patients with an IAD≥15 mmHg were at similar risk of all measures outcomes except for higher risk for stroke, compared to patients with an IAD<15 mmHg. Furthermore, dual pathway antithrombotic regimen compared with aspirin alone produced consistent reductions in MACE and MALE events irrespective of IAD. Thus, based on these data, measuring IAD for risk stratification purposes does not appear to be useful in patients with established vascular disease – an interpretation supported by exploratory analyses suggesting that IAD predicts outcome in patients with less advanced disease (normal ABI, fewer high risk criteria) but not in those with more advanced disease.
Systolic IAD has previously been associated with increased risk of cardiovascular events and mortality in patients with hypertension [
]. Clark et al., in a pooled meta-analysis of ∼57,000 individuals, showed a significant association between systolic IAD and all-cause mortality, cardiovascular mortality, and cardiovascular events [
Associations between systolic interarm differences in blood pressure and cardiovascular disease outcomes and mortality: Individual participant data meta-analysis, development and validation of a prognostic algorithm: the interpress-ipd collaboration.
]. However, our data starkly contrasted these findings and suggested that measuring IAD for cardiovascular risk prediction is not useful in patients with established vascular disease (perhaps with the exception of stroke - an association that has previously been established within the scientific literature [
Inter-arm systolic blood pressure differences, relations with future vascular events and mortality in patients with and without manifest vascular disease.
]). The differences between the studies may be because we only included patients with chronic vascular disease, whereas most prior studies included individuals without vascular disease, with the exception of Aboyans et al., who demonstrated that subclavian stenosis was not associated with significant increase in risk in patients with a history of CVD, which is in line with our findings [
In addition to questioning the clinical validity and significance of measuring IAD in vascular disease patients, the authors urge the cautionary interpretation of IAD. Previous studies have highlighted the poor reproducibility of IAD >10 mmHg in patients with diabetes [
[measuring the blood pressure in both arms is of little use; longitudinal study into blood pressure differences between both arms and its reproducibility in patients with diabetes mellitus type 2].
]. The inconsistency that is associated with measuring intra arm blood pressure differences has caused some to question the relevancy of the measurement [
]; therefore, utilizing the ankle brachial index along with clinical history and physical exam remains highly recommended when identifying patients with established vascular disease. Notably, our findings remained consistent even after using an IAD cutoff of 10 mmHg.
Among the 27,395 patients enrolled in the COMPASS trial, 11.3% of patients were found to have an IAD>15 mm Hg. After stratifying patients based on their CAD and PAD status, prevalence of IAD>15 mmHg were 10.4% and 13.5%, respectively – comparable or higher to previous studies (8.8%) [
]. Differences in prevalence rates compared to our findings could be attributed to the previously established lack of reproducibility and consistency of Interarm blood pressure difference measurement in patients with vascular disease [
The reasons for the increased stroke rate in patients with IAD ≥15 mmHg is yet to be fully understood, but numerous etiologies may explain the phenomena. These include embolic events stemming from the heart and carotid arteries, anatomical reasons, as well as hemodynamic causes. Furthermore, the pathophysiology that gives rise to systolic IAD in the upper extremities is also yet to be completely understood. However, studies suggest that anatomical and hemodynamic changes play a major role [
]. Moreover, an IAD may also reflect atherosclerotic disease within the subclavian or brachiocephalic artery (most common cause and a direct source of stroke), but in some cases, the etiology may be due to other pathologies such as connective tissue disorders, radiation arteritis, thoracic outlet compression, dissecting aortic aneurysm, atrial fibrillation, atherosclerosis of the thoracic aorta, subclavian steal syndrome, and congenital abnormalities [
Measuring blood pressure using blood pressure monitoring devices is routinely implemented within clinical practice. However, BP measurement of only one arm is more widely practiced, with variations in arm pressures often overlooked despite its indication of vascular disease and death [
]. Unlike primary prevention settings, our results suggest that measuring IAD for risk stratification purposes is not useful in patients with established vascular disease.
This study has a few limitations. Firstly, in this investigation, only 10% of patients had an IAD ≥15 mmHg, but still included a sizeable patient cohort and aligned with previous findings [
] Nonetheless, both groups had similar reductions in MACE and MALE outcomes when comparing the dual compass regimen to aspirin alone. Secondly, the majority of patients enrolled within the COMPASS trial were aggressively managed with best medical management (statin therapy and renin angiotensin aldosterone–system inhibitors), which has been demonstrated to reduce cardiovascular events. Such optimization of cardiovascular risk factors may not be observed within routine clinical practice, thereby affecting the generalizability of our results. Thirdly, it is possible that some of our findings could be attributed to chance. Fourthly, serial blood pressure measurements were not performed. Finally, additional vascular imaging was performed only in a subset of patients enrolled post CABG and did not extend to arterial supply to the upper limbs.
In conclusion, our data reports that measuring IAD for risk stratification purposes does not appear to be useful in patients with established atherosclerotic disease.
Financial support
The COMPASS trial was funded by Bayer AG.
CRediT authorship contribution statement
Mohammad Qadura: Concept and design, Funding acquisition, Acquisition, Formal analysis, analysis, or interpretation of data, Writing – original draft, Drafting of the manuscript, Critical revision of the manuscript for important intellectual content, Final Manuscript Approval. Muzammil H. Syed: Funding acquisition, Acquisition, Formal analysis, analysis, or interpretation of data, Writing – original draft, Drafting of the manuscript, Critical revision of the manuscript for important intellectual content, Final Manuscript Approval. Sonia Anand: Funding acquisition, Concept and design, Acquisition, Formal analysis, analysis, or interpretation of data, Critical revision of the manuscript for important intellectual content, Final Manuscript Approval. Jackie Bosch: Funding acquisition, Concept and design, Acquisition, Formal analysis, analysis, or interpretation of data, Critical revision of the manuscript for important intellectual content, Final Manuscript Approval. Stuart Connolly: Funding acquisition, Concept and design, Formal analysis, Acquisition, analysis, or interpretation of data, Critical revision of the manuscript for important intellectual content, Final Manuscript Approval. Victor Aboyans: Funding acquisition, Acquisition, Formal analysis, analysis, or interpretation of data, Critical revision of the manuscript for important intellectual content, Final Manuscript Approval. Eva Muehlhofer: Funding acquisition, Acquisition, Formal analysis, analysis, or interpretation of data, Critical revision of the manuscript for important intellectual content, Final Manuscript Approval. Salim Yusuf: Funding acquisition, Concept and design, Formal analysis, Acquisition, analysis, or interpretation of data, Critical revision of the manuscript for important intellectual content, Final Manuscript Approval. John Eikelboom: Funding acquisition, Concept and design, Formal analysis, Acquisition, analysis, or interpretation of data, Writing – original draft, Drafting of the manuscript, Critical revision of the manuscript for important intellectual content, Final Manuscript Approval.
Declaration of competing interest
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr Connolly reports personal fees from BMS, Bayer, Boehringer Ingelheim, Daiichi Sankyo, and Portola during the conduct of the study. k. Dr Bosch reported receiving honararium and salary support for conducting research from Bayer. Dr. Eikelboom reports honoraria and grant support from Astra Zeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb/Pfizer, Daiichi-Sankyo, GlaxoSmithKline, Janssen, Sanofi Aventis, and Eli Lilly as well as a personnel award from the Heart and Stroke Foundation. Dr. Anand, receiving lecture fees from Bayer and Janssen. Dr Muehlhofer, being employed by Bayer. Dr Aboyans reports grants and/or honoraria for speaking and consulting from Bayer, Bristol Myers Squibb, Novartis, and Pfizer and personal fees from Boehringer Ingelheim, Amgen, and Bristol Myers Squibb/Pfizer Alliance. Dr. Yusuf reported grants and personal fees from and has received research grants and honoraria and travel reimbursement for speaking from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, AstraZeneca, Cadila Pharmaceuticals, and Sanofi Aventis.
Appendix A. Supplementary data
The following is the Supplementary data to this article:
Disability-adjusted life years (dalys) for 291 diseases and injuries in 21 regions, 1990–2010: a systematic analysis for the global burden of disease study 2010.
Age-and sex-specific burden of cardiovascular disease attributable to 5 major and modifiable risk factors in 10 asian countries of the western pacific region.
Global, regional, and national age-sex specific mortality for 264 causes of death, 1980–2016: a systematic analysis for the global burden of disease study 2016.
acc/aha/aapa/abc/acpm/ags/apha/ash/aspc/nma/pcna guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the american college of cardiology/american heart association task force on clinical practice guidelines.
esh/esc practice guidelines for the management of arterial hypertension: Esh-esc the task force for the management of arterial hypertension of the european society of hypertension (esh) and of the european society of cardiology (esc).
Association of an inter-arm systolic blood pressure difference with all-cause and cardiovascular mortality: an updated meta-analysis of cohort studies.
Associations between systolic interarm differences in blood pressure and cardiovascular disease outcomes and mortality: Individual participant data meta-analysis, development and validation of a prognostic algorithm: the interpress-ipd collaboration.
Inter-arm systolic blood pressure differences, relations with future vascular events and mortality in patients with and without manifest vascular disease.
[measuring the blood pressure in both arms is of little use; longitudinal study into blood pressure differences between both arms and its reproducibility in patients with diabetes mellitus type 2].
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