The Difference in Blood Pressure Between Arms and Survival
The Difference in Blood Pressure Between Arms and Survival
A difference in systolic blood pressure between arms of 10 mm Hg or more or 15 mm Hg or more in people with hypertension in primary care was associated with a reduction in event free survival over 10 years. This association held for the study population when participants with pre-existing cardiovascular disease were included or excluded and, compared with our earlier analysis at 4.7 years’ follow-up, the survival curves have continued to diverge. The presence of an interarm difference in systolic blood pressure of 10 mm Hg or more in participants not known to have cardiovascular disease at recruitment but with a high cardiovascular risk score of more than 20% at baseline, seems to confer a level of risk for events of similar magnitude to that of participants with previously diagnosed cardiovascular disease.
One investigator (CEC) gathered all the data. In designing this study, a sequential method of measurement was chosen as a pragmatic test within the consultation. A recent meta-analysis has suggested that a simultaneous, automated repeated measurement method with one or two machines should be the ideal for epidemiological study, and we also, subsequent to establishing this study, showed that a simultaneous measurement technique reduces bias. Studies relevant to the general population using such techniques have reported lower prevalences of an interarm difference in blood pressure than those using sequential measurements. However, subsequent sampling of the study cohort presented here, using a robust simultaneous measurement technique, showed similar prevalence rates for interarm differences of 10 mm Hg or more of 19% for systolic blood pressure and 7% for diastolic blood pressure (compared with the 23% and 6% reported here). One study also reported a strong correlation of interarm differences when comparing three simultaneous and three sequentially gathered pairs of readings, and a correlation remained when measurements were repeated at a later date. We have presented data suggesting that a single sequential pair of measurements can reliably rule out an interarm difference in blood pressure with high negative predictive value, and our new meta-analysis has shown no difference in the strength of association between peripheral vascular disease and systolic interarm differences in blood pressure according to the method of measurement. Given current knowledge, if designing this study now we would adopt an automated simultaneous measurement method, although we believe that our pragmatic approach remains relevant to “real world” practice.
The lack of strict randomisation of the order of arm measurement could have introduced bias, as blood pressure measurements will often decrease during repetition. No strict first arm preference was adopted, however, and the small absolute difference in blood pressure in favour of right or left arms is in keeping with previously reported large series and suggests that no systematic bias was introduced. The investigator CEC was not blinded to data collection, but because events were recorded prospectively over 10 years, and our definitions of non-fatal events required independent diagnosis in secondary care, we do not believe that this lack of blinding could have biased the survival outcomes reported. We did not collect data on drug use at recruitment or changes in use during the study period, so cannot comment on potential survival differences due to drugs.
This is a small study from one rural general practice. The reported prevalence of participants receiving treatment for hypertension in this study was 14.3% of the list, comparable to the 13.7% for women and 11.7% for men reported at the time by the health survey for England. Therefore we believe that these findings can be generalised to other similar cohorts of people with hypertension being treated in primary care, although the lack of representation of ethnic minority groups in Devon is a recognised limitation. Conversely, this rural practice has a low turnover of patients, facilitating long term follow-up, which we see as a strength.
Based on the previous analysis of this cohort, giving a hazard ratio of 2.5 for the composite outcome of mortality or event at a cut-off point for interarm difference in systolic blood pressure of 10 mm Hg, we estimated that we would have required a total of 50 observed events to achieve 90% power and 62 to achieve 95% power. In this follow-up we observed 108 deaths or events. Higher cut-off values were initially included in the analysis plan to permit comparison with other survival studies; however, the diminishing numbers of participants with an interarm difference in systolic blood pressure of more than 15 mm Hg meant a reduced precision of the event results for higher interarm differences, these analyses are therefore not included in the data presented.
Prevalence of an interarm difference in blood pressure varies with the population studied and tends to be higher in the presence of hypertension. Whether this reflects a truly higher prevalence or is merely a function of higher achievement of an arbitrary cut-off point where absolute values are increased is unclear, but the prevalence values reported here are consistent with our previous meta-analysis of similar cohorts measured with robust techniques.
Some previous series have suggested a bias towards higher readings from the right arm, whereas others have failed to show this; studies looking specifically at left or right handedness have also failed to show an association with the arm producing the higher reading. This study has not found a consistent bias to one side for interarm differences in either systolic or diastolic blood pressures, and shows that measurement using both arms at initial assessment is required to avoid future underestimation of blood pressure owing to an unrecognised difference between arms. In fact the direction of mean differences in systolic and diastolic blood pressures was opposite, in keeping with some other reported series, and we suggest this may be related to differing pulse pressures along the aorta. Current guidance suggests that an interarm difference of less than 10 mm Hg can be considered to be normal and that differences of 20/10 mm Hg or more warrant specialist referral. Previous studies have proposed a normal range for differences in systolic or diastolic blood pressure of up to 10 mm Hg and it has been argued from other cross sectional series that the high prevalence of differences above these cut-off points implies that this is a physiological rather than a pathological finding. Our recent meta-analysis has, however, shown that an interarm difference in systolic blood pressure of 10 mm Hg or more or 15 mm Hg or more is associated with peripheral vascular disease in cross sectional studies, with a pooled risk ratio of 2.4 or 2.5, respectively. Peripheral vascular disease is recognised as a risk factor for future cardiovascular events and mortality, and we have previously proposed that an interarm difference in blood pressure is due to peripheral vascular disease. An interarm difference in systolic blood pressure of 15 mm Hg or more is associated with angiographic evidence of carotid or aortic artery disease, and vascular disease of the arms is associated with hypertension. Thus evidence supports the association of an interarm difference with existing peripheral vascular disease, and we propose that this accounts for the survival differences seen.
Two other prospective studies have reported increased mortality with an interarm difference in systolic blood pressure; the larger study reported a significant survival difference with a difference of 15 mm Hg or more. Three cohorts were combined in that paper and differences were not significant for the cohort recruited from the community; only total deaths were significantly higher in one of the two cohorts recruited from vascular clinics. The other study, of renal and general medical out-patients, showed significantly higher rates of events or death for an interarm difference in systolic blood pressure of 10 mm Hg or more. Meta-analysis to combine data for an interarm difference in systolic blood pressure of 15 mm Hg or more presented here with three other cohorts was possible and showed pooled hazard ratios for all cause mortality of 1.6 (95% confidence interval 1.1 to 2.3) and for cardiovascular related mortality of 1.7 (1.1 to 2.5). Thus there is supporting evidence from other studies that an interarm difference in blood pressure is a predictor of cardiovascular events and death in populations at high baseline cardiovascular risk.
Guidelines advocate the measurement of blood pressure in both arms as part of the initial assessment of hypertension. Failure to recognise a difference can lead to underestimation or under-treatment of blood pressure, but this guidance is not routinely followed in primary care and the additional time required to measure both arms has been cited as a practical problem. It is postulated that this poor uptake may be due in part to a lack of evidence thought to be relevant by primary care practitioners, and guidelines should make use of available evidence rather than consensus views where evidence does exist. The finding here of an additional cardiovascular risk associated with an interarm difference in a representative primary care cohort with hypertension is therefore important. In this study, regression modelling showed the interarm difference to be an independent variable associated with increased risk of events or death, and in stratified analysis its presence conferred a risk equivalent to established cardiovascular disease. This would suggest that those with an interarm difference may justifiably require aggressive management along secondary prevention guidelines, such as the addition of statin therapy, and potentially by adding antiplatelet treatment to their care; a strategy that remains of unclear benefit in primary cardiovascular prevention. This seems a logical and pathologically plausible proposal since such treatment is effective in secondary prevention and therefore ought to be effective in primary prevention for selected cases at the highest vascular risk; however, further work is needed to justify this approach. We have suggested that the interarm difference is a manifestation of occult peripheral vascular disease, which is known to confer an increased risk of events or death and is therefore managed with aggressive lifestyle and drug strategies. Non-invasive studies have repeatedly shown an association of interarm differences in systolic blood pressure of 10 mm Hg or more and 15 mm Hg or more with peripheral vascular disease, and we consider that confirmation of an interarm difference may indicate that further assessment for the presence of peripheral vascular disease should be undertaken. To date, however, there are no studies of relevant interventions on which to base clinical recommendations.
This study adds important information to the evidence base supporting the need to detect an interarm difference in blood pressure, not only to improve measurement and management of hypertension but to consider the vascular risk to the patient. The interarm difference in blood pressure has the potential to act as a simple non-invasive test, identifying those who could benefit from more intensive assessment—for example, by measurement of ankle-brachial pressure index. This measurement is not routinely undertaken in the primary care assessment of patients with hypertension and is not included in the NHS health check programme. It requires time, experience, and training, whereas bilateral brachial blood pressure measurements can be easily taken. Therefore, further studies of the association of interarm differences in blood pressure with other manifestations of peripheral and cardiovascular disease, in cohorts representative of the primary care population, would be valuable.
An interarm difference in systolic blood pressure of 10 mm Hg or more or 15 mm Hg or more predicts reduced mortality and event free survival over 10 years in people with hypertension in primary care. This study supports the potential value of an interarm difference as a simple clinical indicator of increased cardiovascular risk. Assessment of blood pressure in both arms is recommended by guidelines and should become a core component of initial blood pressure measurement in primary care. Detection of an interarm difference should prompt consideration of further vascular assessment and aggressive management of risk factors.
Discussion
A difference in systolic blood pressure between arms of 10 mm Hg or more or 15 mm Hg or more in people with hypertension in primary care was associated with a reduction in event free survival over 10 years. This association held for the study population when participants with pre-existing cardiovascular disease were included or excluded and, compared with our earlier analysis at 4.7 years’ follow-up, the survival curves have continued to diverge. The presence of an interarm difference in systolic blood pressure of 10 mm Hg or more in participants not known to have cardiovascular disease at recruitment but with a high cardiovascular risk score of more than 20% at baseline, seems to confer a level of risk for events of similar magnitude to that of participants with previously diagnosed cardiovascular disease.
Strengths and Limitations of the Study
One investigator (CEC) gathered all the data. In designing this study, a sequential method of measurement was chosen as a pragmatic test within the consultation. A recent meta-analysis has suggested that a simultaneous, automated repeated measurement method with one or two machines should be the ideal for epidemiological study, and we also, subsequent to establishing this study, showed that a simultaneous measurement technique reduces bias. Studies relevant to the general population using such techniques have reported lower prevalences of an interarm difference in blood pressure than those using sequential measurements. However, subsequent sampling of the study cohort presented here, using a robust simultaneous measurement technique, showed similar prevalence rates for interarm differences of 10 mm Hg or more of 19% for systolic blood pressure and 7% for diastolic blood pressure (compared with the 23% and 6% reported here). One study also reported a strong correlation of interarm differences when comparing three simultaneous and three sequentially gathered pairs of readings, and a correlation remained when measurements were repeated at a later date. We have presented data suggesting that a single sequential pair of measurements can reliably rule out an interarm difference in blood pressure with high negative predictive value, and our new meta-analysis has shown no difference in the strength of association between peripheral vascular disease and systolic interarm differences in blood pressure according to the method of measurement. Given current knowledge, if designing this study now we would adopt an automated simultaneous measurement method, although we believe that our pragmatic approach remains relevant to “real world” practice.
The lack of strict randomisation of the order of arm measurement could have introduced bias, as blood pressure measurements will often decrease during repetition. No strict first arm preference was adopted, however, and the small absolute difference in blood pressure in favour of right or left arms is in keeping with previously reported large series and suggests that no systematic bias was introduced. The investigator CEC was not blinded to data collection, but because events were recorded prospectively over 10 years, and our definitions of non-fatal events required independent diagnosis in secondary care, we do not believe that this lack of blinding could have biased the survival outcomes reported. We did not collect data on drug use at recruitment or changes in use during the study period, so cannot comment on potential survival differences due to drugs.
This is a small study from one rural general practice. The reported prevalence of participants receiving treatment for hypertension in this study was 14.3% of the list, comparable to the 13.7% for women and 11.7% for men reported at the time by the health survey for England. Therefore we believe that these findings can be generalised to other similar cohorts of people with hypertension being treated in primary care, although the lack of representation of ethnic minority groups in Devon is a recognised limitation. Conversely, this rural practice has a low turnover of patients, facilitating long term follow-up, which we see as a strength.
Based on the previous analysis of this cohort, giving a hazard ratio of 2.5 for the composite outcome of mortality or event at a cut-off point for interarm difference in systolic blood pressure of 10 mm Hg, we estimated that we would have required a total of 50 observed events to achieve 90% power and 62 to achieve 95% power. In this follow-up we observed 108 deaths or events. Higher cut-off values were initially included in the analysis plan to permit comparison with other survival studies; however, the diminishing numbers of participants with an interarm difference in systolic blood pressure of more than 15 mm Hg meant a reduced precision of the event results for higher interarm differences, these analyses are therefore not included in the data presented.
Comparison With Existing Literature
Prevalence of an interarm difference in blood pressure varies with the population studied and tends to be higher in the presence of hypertension. Whether this reflects a truly higher prevalence or is merely a function of higher achievement of an arbitrary cut-off point where absolute values are increased is unclear, but the prevalence values reported here are consistent with our previous meta-analysis of similar cohorts measured with robust techniques.
Some previous series have suggested a bias towards higher readings from the right arm, whereas others have failed to show this; studies looking specifically at left or right handedness have also failed to show an association with the arm producing the higher reading. This study has not found a consistent bias to one side for interarm differences in either systolic or diastolic blood pressures, and shows that measurement using both arms at initial assessment is required to avoid future underestimation of blood pressure owing to an unrecognised difference between arms. In fact the direction of mean differences in systolic and diastolic blood pressures was opposite, in keeping with some other reported series, and we suggest this may be related to differing pulse pressures along the aorta. Current guidance suggests that an interarm difference of less than 10 mm Hg can be considered to be normal and that differences of 20/10 mm Hg or more warrant specialist referral. Previous studies have proposed a normal range for differences in systolic or diastolic blood pressure of up to 10 mm Hg and it has been argued from other cross sectional series that the high prevalence of differences above these cut-off points implies that this is a physiological rather than a pathological finding. Our recent meta-analysis has, however, shown that an interarm difference in systolic blood pressure of 10 mm Hg or more or 15 mm Hg or more is associated with peripheral vascular disease in cross sectional studies, with a pooled risk ratio of 2.4 or 2.5, respectively. Peripheral vascular disease is recognised as a risk factor for future cardiovascular events and mortality, and we have previously proposed that an interarm difference in blood pressure is due to peripheral vascular disease. An interarm difference in systolic blood pressure of 15 mm Hg or more is associated with angiographic evidence of carotid or aortic artery disease, and vascular disease of the arms is associated with hypertension. Thus evidence supports the association of an interarm difference with existing peripheral vascular disease, and we propose that this accounts for the survival differences seen.
Two other prospective studies have reported increased mortality with an interarm difference in systolic blood pressure; the larger study reported a significant survival difference with a difference of 15 mm Hg or more. Three cohorts were combined in that paper and differences were not significant for the cohort recruited from the community; only total deaths were significantly higher in one of the two cohorts recruited from vascular clinics. The other study, of renal and general medical out-patients, showed significantly higher rates of events or death for an interarm difference in systolic blood pressure of 10 mm Hg or more. Meta-analysis to combine data for an interarm difference in systolic blood pressure of 15 mm Hg or more presented here with three other cohorts was possible and showed pooled hazard ratios for all cause mortality of 1.6 (95% confidence interval 1.1 to 2.3) and for cardiovascular related mortality of 1.7 (1.1 to 2.5). Thus there is supporting evidence from other studies that an interarm difference in blood pressure is a predictor of cardiovascular events and death in populations at high baseline cardiovascular risk.
Implications for Clinical Practice
Guidelines advocate the measurement of blood pressure in both arms as part of the initial assessment of hypertension. Failure to recognise a difference can lead to underestimation or under-treatment of blood pressure, but this guidance is not routinely followed in primary care and the additional time required to measure both arms has been cited as a practical problem. It is postulated that this poor uptake may be due in part to a lack of evidence thought to be relevant by primary care practitioners, and guidelines should make use of available evidence rather than consensus views where evidence does exist. The finding here of an additional cardiovascular risk associated with an interarm difference in a representative primary care cohort with hypertension is therefore important. In this study, regression modelling showed the interarm difference to be an independent variable associated with increased risk of events or death, and in stratified analysis its presence conferred a risk equivalent to established cardiovascular disease. This would suggest that those with an interarm difference may justifiably require aggressive management along secondary prevention guidelines, such as the addition of statin therapy, and potentially by adding antiplatelet treatment to their care; a strategy that remains of unclear benefit in primary cardiovascular prevention. This seems a logical and pathologically plausible proposal since such treatment is effective in secondary prevention and therefore ought to be effective in primary prevention for selected cases at the highest vascular risk; however, further work is needed to justify this approach. We have suggested that the interarm difference is a manifestation of occult peripheral vascular disease, which is known to confer an increased risk of events or death and is therefore managed with aggressive lifestyle and drug strategies. Non-invasive studies have repeatedly shown an association of interarm differences in systolic blood pressure of 10 mm Hg or more and 15 mm Hg or more with peripheral vascular disease, and we consider that confirmation of an interarm difference may indicate that further assessment for the presence of peripheral vascular disease should be undertaken. To date, however, there are no studies of relevant interventions on which to base clinical recommendations.
Implications for Future Research
This study adds important information to the evidence base supporting the need to detect an interarm difference in blood pressure, not only to improve measurement and management of hypertension but to consider the vascular risk to the patient. The interarm difference in blood pressure has the potential to act as a simple non-invasive test, identifying those who could benefit from more intensive assessment—for example, by measurement of ankle-brachial pressure index. This measurement is not routinely undertaken in the primary care assessment of patients with hypertension and is not included in the NHS health check programme. It requires time, experience, and training, whereas bilateral brachial blood pressure measurements can be easily taken. Therefore, further studies of the association of interarm differences in blood pressure with other manifestations of peripheral and cardiovascular disease, in cohorts representative of the primary care population, would be valuable.
Conclusions
An interarm difference in systolic blood pressure of 10 mm Hg or more or 15 mm Hg or more predicts reduced mortality and event free survival over 10 years in people with hypertension in primary care. This study supports the potential value of an interarm difference as a simple clinical indicator of increased cardiovascular risk. Assessment of blood pressure in both arms is recommended by guidelines and should become a core component of initial blood pressure measurement in primary care. Detection of an interarm difference should prompt consideration of further vascular assessment and aggressive management of risk factors.
Source...