Beta-Blockade in Patients With Abdominal Aortic Aneurysms
Beta-Blockade in Patients With Abdominal Aortic Aneurysms
We found that, in patients with AAA, beta blockade led to no significant improvement in our primary outcome measures V̇O2 at
or peak (albeit the increase in V̇ O2 at
fell just short of statistical significance) but did have a significant impact on the other exploratory CPET variables. Beta-blockade improved exercise performance evidenced by a significantly increased workload at
, decreased heart rate and V̇ E/V̇ CO2 at both
and peak exercise, and increased O 2 pulse at
and at peak. The primary determinant of the increase in O 2 pulse both at
and peak exercise was the decrease in heart rate. Additionally, we found that patients who were chronically beta-blocked had generally worse performance on CPET, regardless of whether the CPET is performed on or off medications. This finding was independent of the presence of any cardiac disease.
The findings of our study mirror the complex effects that beta-blockers are known to have on cardio-respiratory physiology, albeit predominantly in patients with cardiac failure. Beyond the well-known effects on cardiac function, beta-blockers cause increased O2 extraction but not increased V̇O2 during exercise, in keeping with our findings. Beta-blockers, as we found in our patients, improve V̇E/V̇CO2, an effect mediated by β1 and, in particular, β2 adrenergic receptors, whose blockade improves diffusion capacity. In contrast the effect of beta-blockers on healthy individuals is opposite, with reduced V̇O2, exercise tolerance and ventilatory equivalents. Hence, the behaviour of our patients resembled the expected response pattern of a population with cardiac failure rather than healthy volunteers. To our knowledge this is the first study to investigate the impact of beta-blockade on CPET performance in a preoperative setting, studying elderly patients with a significant prevalence of cardiovascular risk factors, but a low prevalence of overt cardiac failure.
As CPET is commonly and increasingly used in the preoperative assessment of these patients, clinicians must decide whether to perform the test on or off beta-blockers. Beta-blockade during CPET reduces the test's ability to detect significant myocardial ischaemia, an important prognostic indicator. However, it is logical to assess the patient under conditions experienced during and after surgery, when beta-blockade is recommended to be continued to avoid cardiac complications. Acute beta-blockade before vascular surgery has been widely used to prevent perioperative myocardial ischaemia, although its benefit is often offset by an increased incidence of non-cardiac complications. Our study shows that a CPET test performed whilst on beta-blockers will lead to a somewhat 'better' exercise performance than if the test is done off the medications. Hence, if perioperative acute beta-blockade is usual practice the preoperative test should probably be performed on beta-blockers. Data in Figure 2 shows a variation in individual patient parameters; especially V̇O2 Peak (Panel B); however, we were unable to identify specific characteristics which would explain these individual variations. A larger study would be needed to investigate these potentially important variations.
Beta-blockers are often used chronically by patients undergoing aortic surgery, as these individuals have a high prevalence of ischaemic heart disease, hypertension, cardiac failure and arrhythmias (as evidenced by our cohort). In general, this cohort display worse exercise performance than those not on long-term beta-blocker therapy irrespective of the presence of cardiac disease. However, the effect of beta-blockade is similar and there appears no reason to withdraw the beta-blocker before preoperative CPET testing. The decision to initiate perioperative beta-blockade and its relationship to surgical outcomes and survival remains, in many cases, highly controversial and beyond the scope of this study.
Strengths of this study include the robust methodology by which the CPET was performed. CPET interpretation was carried out in a blinded fashion by 2 experienced clinicians (with a high degree of interobserver agreement), with resolution of any discrepancies by a third experienced clinician scientist. All resting CPET data were taken between minute 2 and 3 to negate the effects of any acute hyperventilation. The patient cohort was an unselected group of AAA patients under surveillance which readily mimic a typical perioperative vascular patient cohort. Finally, the significantly lower heart rate in subjects taking beta-blockers, regardless of whether prescribed normally shows that the protocol produced an appropriate physiological response.
Potential limitations include the use of different medications at different dosages by chronically beta-blocked patients, with differing degrees of cardioselectivity and intrinsic sympathomimetic activity. This group was formed by patients in whom medical therapy was deemed adequate by their treating physicians, and represents a typical population encountered in a preoperative assessment setting. In clinical practice it would be unusual to switch the specific beta-blocker before surgery so our 'pragmatic' protocol closely reflects real practice. For acute beta-blockade, we chose bisoprolol because it is a highly selective β1 blocker, off patent and most commonly used in local clinical practice (as seen in the 'chronic' group). We do not believe that a different medication would have produced a markedly different effect but we cannot rule this out. Although the subjects showed a reduction in heart rate with beta-blockade the degree of beta-blockade will have been variable in between patients. Furthermore, there was scope to further increase the beta-blocker dose in some patients and this could have potentiated any effect on exercise performance. However, our study mirrors real life practice where this titration would not be routine.
Although we saw a trend towards higher V̇O2 values with beta-blockers, we could not demonstrate a statistically significant difference, possibly because of too small a sample size (albeit adequately powered, according to our assumptions and previously published data). Larger numbers would also be necessary to study the interactions of beta-blockers with other cardiorespiratory medications, which we did not evaluate, and may help to explain the different responses of individual patients. A much larger study would also be necessary to identify patients' characteristics associated with a 'positive' response to beta-blockade.
We have shown that only a small number of subjects were diagnosed with or treated for COPD although the presence of airflow obstruction (mostly mild) was common, suggesting significant under-diagnosis. However, in both the acute and chronic groups commencement of beta-blockers had little effect on spirometric measures of airflow obstruction (FEV1 and FEV1/FVC).
Our study shows that, in patients with AAA, beta-blockade improved exercise performance evidenced by a significantly increased workload at
, decreased heart rate and V̇ E/V̇ CO2 at both
and peak exercise. Although a significant difference was seen in the O 2 pulse at
and peak exercise, this was as a result of a change in heart rate and not a change in V̇ O2. Furthermore, we did not demonstrate a significant difference in V̇ O2 at
or peak. Patients already taking long term beta-blocker therapy were generally less physically fit both whilst taking long term beta-blockers and when these were stopped. In light of this we suggest that beta-blockade before/during preoperative CPET testing should mirror the perioperative practice of the centre. This study may also guide clinicians in charge of the perioperative management of such patients as to likely CPET response on and off beta-blocker treatment.
Discussion
We found that, in patients with AAA, beta blockade led to no significant improvement in our primary outcome measures V̇O2 at
or peak (albeit the increase in V̇ O2 at
fell just short of statistical significance) but did have a significant impact on the other exploratory CPET variables. Beta-blockade improved exercise performance evidenced by a significantly increased workload at
, decreased heart rate and V̇ E/V̇ CO2 at both
and peak exercise, and increased O 2 pulse at
and at peak. The primary determinant of the increase in O 2 pulse both at
and peak exercise was the decrease in heart rate. Additionally, we found that patients who were chronically beta-blocked had generally worse performance on CPET, regardless of whether the CPET is performed on or off medications. This finding was independent of the presence of any cardiac disease.
The findings of our study mirror the complex effects that beta-blockers are known to have on cardio-respiratory physiology, albeit predominantly in patients with cardiac failure. Beyond the well-known effects on cardiac function, beta-blockers cause increased O2 extraction but not increased V̇O2 during exercise, in keeping with our findings. Beta-blockers, as we found in our patients, improve V̇E/V̇CO2, an effect mediated by β1 and, in particular, β2 adrenergic receptors, whose blockade improves diffusion capacity. In contrast the effect of beta-blockers on healthy individuals is opposite, with reduced V̇O2, exercise tolerance and ventilatory equivalents. Hence, the behaviour of our patients resembled the expected response pattern of a population with cardiac failure rather than healthy volunteers. To our knowledge this is the first study to investigate the impact of beta-blockade on CPET performance in a preoperative setting, studying elderly patients with a significant prevalence of cardiovascular risk factors, but a low prevalence of overt cardiac failure.
As CPET is commonly and increasingly used in the preoperative assessment of these patients, clinicians must decide whether to perform the test on or off beta-blockers. Beta-blockade during CPET reduces the test's ability to detect significant myocardial ischaemia, an important prognostic indicator. However, it is logical to assess the patient under conditions experienced during and after surgery, when beta-blockade is recommended to be continued to avoid cardiac complications. Acute beta-blockade before vascular surgery has been widely used to prevent perioperative myocardial ischaemia, although its benefit is often offset by an increased incidence of non-cardiac complications. Our study shows that a CPET test performed whilst on beta-blockers will lead to a somewhat 'better' exercise performance than if the test is done off the medications. Hence, if perioperative acute beta-blockade is usual practice the preoperative test should probably be performed on beta-blockers. Data in Figure 2 shows a variation in individual patient parameters; especially V̇O2 Peak (Panel B); however, we were unable to identify specific characteristics which would explain these individual variations. A larger study would be needed to investigate these potentially important variations.
Beta-blockers are often used chronically by patients undergoing aortic surgery, as these individuals have a high prevalence of ischaemic heart disease, hypertension, cardiac failure and arrhythmias (as evidenced by our cohort). In general, this cohort display worse exercise performance than those not on long-term beta-blocker therapy irrespective of the presence of cardiac disease. However, the effect of beta-blockade is similar and there appears no reason to withdraw the beta-blocker before preoperative CPET testing. The decision to initiate perioperative beta-blockade and its relationship to surgical outcomes and survival remains, in many cases, highly controversial and beyond the scope of this study.
Strengths of this study include the robust methodology by which the CPET was performed. CPET interpretation was carried out in a blinded fashion by 2 experienced clinicians (with a high degree of interobserver agreement), with resolution of any discrepancies by a third experienced clinician scientist. All resting CPET data were taken between minute 2 and 3 to negate the effects of any acute hyperventilation. The patient cohort was an unselected group of AAA patients under surveillance which readily mimic a typical perioperative vascular patient cohort. Finally, the significantly lower heart rate in subjects taking beta-blockers, regardless of whether prescribed normally shows that the protocol produced an appropriate physiological response.
Potential limitations include the use of different medications at different dosages by chronically beta-blocked patients, with differing degrees of cardioselectivity and intrinsic sympathomimetic activity. This group was formed by patients in whom medical therapy was deemed adequate by their treating physicians, and represents a typical population encountered in a preoperative assessment setting. In clinical practice it would be unusual to switch the specific beta-blocker before surgery so our 'pragmatic' protocol closely reflects real practice. For acute beta-blockade, we chose bisoprolol because it is a highly selective β1 blocker, off patent and most commonly used in local clinical practice (as seen in the 'chronic' group). We do not believe that a different medication would have produced a markedly different effect but we cannot rule this out. Although the subjects showed a reduction in heart rate with beta-blockade the degree of beta-blockade will have been variable in between patients. Furthermore, there was scope to further increase the beta-blocker dose in some patients and this could have potentiated any effect on exercise performance. However, our study mirrors real life practice where this titration would not be routine.
Although we saw a trend towards higher V̇O2 values with beta-blockers, we could not demonstrate a statistically significant difference, possibly because of too small a sample size (albeit adequately powered, according to our assumptions and previously published data). Larger numbers would also be necessary to study the interactions of beta-blockers with other cardiorespiratory medications, which we did not evaluate, and may help to explain the different responses of individual patients. A much larger study would also be necessary to identify patients' characteristics associated with a 'positive' response to beta-blockade.
We have shown that only a small number of subjects were diagnosed with or treated for COPD although the presence of airflow obstruction (mostly mild) was common, suggesting significant under-diagnosis. However, in both the acute and chronic groups commencement of beta-blockers had little effect on spirometric measures of airflow obstruction (FEV1 and FEV1/FVC).
Our study shows that, in patients with AAA, beta-blockade improved exercise performance evidenced by a significantly increased workload at
, decreased heart rate and V̇ E/V̇ CO2 at both
and peak exercise. Although a significant difference was seen in the O 2 pulse at
and peak exercise, this was as a result of a change in heart rate and not a change in V̇ O2. Furthermore, we did not demonstrate a significant difference in V̇ O2 at
or peak. Patients already taking long term beta-blocker therapy were generally less physically fit both whilst taking long term beta-blockers and when these were stopped. In light of this we suggest that beta-blockade before/during preoperative CPET testing should mirror the perioperative practice of the centre. This study may also guide clinicians in charge of the perioperative management of such patients as to likely CPET response on and off beta-blocker treatment.