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Reducing blood pressure variability to prevent stroke?
Reflection and Reaction
Reducing blood pressure variability to prevent stroke? Published Online March 12, 2010 DOI:10.1016/S14744422(10)70067-3 See Articles page 469 See Comment Lancet 2010; 375: 867–69 See Articles Lancet 2010; 375: 895–905 and 906–15 See Review Lancet 2010; 375: 938–48
Blood pressure is regarded as the crown jewel of modifiable risk factors for stroke prevention.1,2 Blood pressure management has undergone substantial change since the 1940s and 1950s, when many physicians were concerned that blood-pressure lowering might not be safe and thus only treated patients with severe or malignant hypertensive states.3 We now know that lowering of blood pressure in less severe forms of hypertension yields benefits in prevention of cardiovascular disease. Furthermore, risk of cardiovascular disease in people older than 50 years might be increased more by high systolic blood pressure (SBP) than by comparatively raised diastolic blood pressure (DBP).3,4 At present, with the exception of compelling indications for use of specific classes of blood-pressure-lowering drugs, the aim is to get blood pressure to the target goal (eg, <140/90 mm Hg in patients with uncomplicated Panel: Key study findings in relation to blood-pressure variability6 ASCOT-BPLA 1 Group SD SBP was lower in the amlodipine group than in the atenolol group at all follow-up visits, primarily because of lower within-individual visit-to-visit variability 2 Within-visit and 24 h ABPM variability in SBP were lower in the amlodipine group than in the atenolol group 3 From baseline, blood pressure variability was reduced by amlodopine and increased by atenolol 4 The lower risk of stroke with amlodipine than atenolol was abolished by adjusting for within-individual SD of clinic SBP 5 Effects on variability meant that at each follow-up visit the number of patients with SBP less than 130 mm Hg was slightly greater in the atenolol treatment group, but the number of patients with very high SBP was substantially greater in the atenolol group 6 In the ABPM substudy, reduced visit-to-visit variability in clinic SBP had a greater effect on reduced risk of vascular events in the amlodipine group than in the atenolol group MRC trial 1 SD SBP and all measures of within-individual visit-to-visit variability in SBP were increased in the atenolol group compared with the placebo group and the diuretic group during initial follow-up 2 Subsequent temporal trends in variability of blood pressure correlated with stroke risk during follow-up in the atenolol group SBP=systolic blood pressure. ABPM=ambulatory blood-pressure monitoring
448
hypertension or <130/80 mm Hg in patients with diabetes or chronic renal disease),4 but not necessarily to focus on specific drug classes, although some physicians have favoured the use of thiazide-type diuretics as initial therapy.2,4 Recent observations, however, have suggested that the class of drug used might affect the risk of stroke and other cardiovascular diseases.5 In this issue of The Lancet Neurology, Rothwell and colleagues6 provide a thoughtful and provocative perspective on possible opposite effects of β blockers and calcium-channel blockers on variability in blood pressure, which might explain their different effects on risk of stroke. A key question addressed in the Article is why do calcium-channel blockers reduce stroke risk to a greater extent and β blockers to a lesser extent than expected based on observed effects on blood pressure. Central to the authors’ hypothesis is that usual blood pressure might not be an adequate marker of stroke risk, whereas visit-to-visit variability in SBP might be a more powerful predictor of stroke independent of mean SBP. The authors chose two clinical trial databases for study—the AngloScandinavian Cardiac Outcomes Trial Blood Pressure Lowering Arm (ASCOT-BPLA)7,8 and the Medical Research Council (MRC) trial.9 SBP, DBP, and pulse pressure withinindividual visit-to-visit variability were expressed as the standard deviation (SD) and coefficient of variation of readings taken over multiple follow-up visits. Meticulous and thoughtful analyses were done based on initial fall of blood pressure, average successive variability, and residual SD.6 Key findings are listed in the panel. Rothwell and colleagues6 suggest that, although blood pressure-lowering drugs reduce mean blood pressure, variability of blood pressure during treatment with a specific drug might be a significant predictor of whether or not stroke prevention is successfully achieved. Furthermore, an accompanying Review10 reports that the findings might be generalisable by class of bloodpressure-lowering drug. The brain does not tolerate instability of blood pressure or blood pressure variability well: brain atrophy, subcortical lesions, and cognitive impairment might occur as consequences.11,12 Rothwell and colleagues6 make a coherent argument and provide a rationale that drugs that reduce blood pressure variability might be more beneficial than drugs that do not reduce blood pressure www.thelancet.com/neurology Vol 9 May 2010
Reflection and Reaction
variability, and prerandomisation (or pretreatment) runin assessment to test for variability of blood pressure could be informative.6 β adrenergic receptor blockers, such as atenolol, presumably lower blood pressure by decreasing cardiac output, inhibiting release of renin and the production of angiotensin II, possibly reducing norepinephrine release from sympathetic neurons, and decreasing central vasomotor activity.3 These drugs can be effective in young white patients with hypertension, those with resting tachycardia, angina, or previous myocardial infarction, and as add-on therapy in patients with congestive heart failure.3 However, several β blockers (particularly atenolol) are not ideal treatments for hypertension, because they have a reduced ability to protect against stroke, and might cause weight gain, dyslipidaemia, and impaired glucose control.2 Rothwell and colleagues6 are to be congratulated for bringing forth compelling findings that eventually might set the foundation for a major change in our practice of blood pressure treatment for the prevention of stroke or other cardiovascular diseases. Therefore, clinicians should give careful consideration to use of drugs associated with low variability in blood pressure.7 Although major guidelines previously expressed caution about the use of β blockers in patients with hypertension and relegated them as less suitable initial therapy,13 we now have an additional rationale—variability of blood pressure—as to why these drugs might not significantly reduce stroke risk. Finally, central aortic blood pressure has been proposed as a more accurate reflection of loading conditions of the left ventricular myocardium and coronary and cerebral arteries. The findings of Rothwell and colleagues6 might prove particularly important if the theory of central aortic blood pressure does not pan out or if both can be applied in clinical practice in a complementary manner, especially if the types of blood-pressure-lowering drugs that lower
central aortic pressure and blood pressure variability are from the same class or classes. Philip B Gorelick Center for Stroke Research, Department of Neurology and Rehabilitation, University of Illinois College of Medicine at Chicago, Chicago, IL 60612, USA [email protected] I have received consultancy fees for serving as an adviser on blood pressurelowering therapy for Novartis and Daiichi Sankyo and on the cardiovascular study adjudication committee for Pfizer. I received consultancy fees for serving on the Boehringer Ingelheim PRoFESS steering committee and my institution received fees for my service on a Boehringer Ingelheim speakers’ bureau. 1 2 3 4
5 6
7
8
9 10
11 12
13
Gorelick PB. New horizons for stroke prevention: PROGRESS and HOPE. Lancet Neurol 2002; 1: 149–56. Aiyagari V, Gorelick PB. Management of blood pressure for acute and recurrent stroke. Stroke 2009; 40: 2251–56. Moser M. Clinical Management of Hypertension (7th edn). West Islip, NY, USA: Professional Communications, 2004. Chobanian AV, Bakris GL, Black HR, et al, and the National High Blood Pressure Education Program Coordinating Committee. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. The JNC 7 Report. JAMA 2003; 289: 2560–72. Carlberg B, Samuelsson O, Lindholm LJ. Atenolol in hypertension: is it a wise choice? Lancet 2004; 364: 1684–89. Rothwell PM, Howard SC, Dolan E, et al, on behalf of the ASCOT-BPLA and MRC Trial Investigators. Effects of β blockers and calcium-channel blockers on within-individual variability in blood pressure and risk of stroke. Lancet Neurol 2010; published online March 12. DOI:10.1016/S1474-4422(10)70066-1. Dahlof B, Sever PS, Poulter NR, et al, ASCOT Investigators. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet 2005; 366: 895–906. Poulter NR, Wedel H, Dahlöf B, et al, for the ASCOT investigators. Role of blood pressure and other variables in the differential cardiovascular event rates noted in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA). Lancet 2005; 366: 907–13. MRC Working Party. Medical Research Council trial of treatment of hypertension in older adults: principal results. BMJ 1992; 304: 405–12. Rothwell PM. Limitations of the usual blood pressure hypothesis and importance of variability, instability, and episodic hypertension. Lancet 2010; 375: 938–48. Goldstein IB, Bartzokis G, Guthrie D, Shapiro D. Ambulatory blood pressure and the brain: a 5-year follow-up. Neurology 2005; 64: 1846–52. Zuccala G, Onder G, Pedone C, et al, for the GIFA-ONLUS Study Group. Hypotension and cognitive impairment. Selective association in patients with heart failure. Neurology 2001; 57: 1986–92. Williams B. Evolution of hypertensive disease: a revolution in guidelines. Lancet 2006; 368: 6–8.
Lithium time-to-event trial in amyotrophic lateral sclerosis stops early for futility Clinical trials in amyotrophic lateral sclerosis (ALS) remain stuck in a rut: so many trials, such high expectations, such disappointing results. Since the trials of riluzole 15 years ago,1 no new drug for treatment of ALS has been introduced on to the market. Preclinical www.thelancet.com/neurology Vol 9 May 2010
trials using the only available animal model, the highcopy G93A superoxide dismutase 1 (SOD1) transgenic mouse, clearly have poor predictive value with regard to treatment of human sporadic ALS. Several different factors have contributed to the failure of this model:
Published Online April 6, 2010 DOI:10.1016/S14744422(10)70085-5 See Articles page 481
449
Reducing blood pressure variability to prevent stroke? Published Online March 12, 2010 DOI:10.1016/S14744422(10)70067-3 See Articles page 469 See Comment Lancet 2010; 375: 867–69 See Articles Lancet 2010; 375: 895–905 and 906–15 See Review Lancet 2010; 375: 938–48
Blood pressure is regarded as the crown jewel of modifiable risk factors for stroke prevention.1,2 Blood pressure management has undergone substantial change since the 1940s and 1950s, when many physicians were concerned that blood-pressure lowering might not be safe and thus only treated patients with severe or malignant hypertensive states.3 We now know that lowering of blood pressure in less severe forms of hypertension yields benefits in prevention of cardiovascular disease. Furthermore, risk of cardiovascular disease in people older than 50 years might be increased more by high systolic blood pressure (SBP) than by comparatively raised diastolic blood pressure (DBP).3,4 At present, with the exception of compelling indications for use of specific classes of blood-pressure-lowering drugs, the aim is to get blood pressure to the target goal (eg, <140/90 mm Hg in patients with uncomplicated Panel: Key study findings in relation to blood-pressure variability6 ASCOT-BPLA 1 Group SD SBP was lower in the amlodipine group than in the atenolol group at all follow-up visits, primarily because of lower within-individual visit-to-visit variability 2 Within-visit and 24 h ABPM variability in SBP were lower in the amlodipine group than in the atenolol group 3 From baseline, blood pressure variability was reduced by amlodopine and increased by atenolol 4 The lower risk of stroke with amlodipine than atenolol was abolished by adjusting for within-individual SD of clinic SBP 5 Effects on variability meant that at each follow-up visit the number of patients with SBP less than 130 mm Hg was slightly greater in the atenolol treatment group, but the number of patients with very high SBP was substantially greater in the atenolol group 6 In the ABPM substudy, reduced visit-to-visit variability in clinic SBP had a greater effect on reduced risk of vascular events in the amlodipine group than in the atenolol group MRC trial 1 SD SBP and all measures of within-individual visit-to-visit variability in SBP were increased in the atenolol group compared with the placebo group and the diuretic group during initial follow-up 2 Subsequent temporal trends in variability of blood pressure correlated with stroke risk during follow-up in the atenolol group SBP=systolic blood pressure. ABPM=ambulatory blood-pressure monitoring
448
hypertension or <130/80 mm Hg in patients with diabetes or chronic renal disease),4 but not necessarily to focus on specific drug classes, although some physicians have favoured the use of thiazide-type diuretics as initial therapy.2,4 Recent observations, however, have suggested that the class of drug used might affect the risk of stroke and other cardiovascular diseases.5 In this issue of The Lancet Neurology, Rothwell and colleagues6 provide a thoughtful and provocative perspective on possible opposite effects of β blockers and calcium-channel blockers on variability in blood pressure, which might explain their different effects on risk of stroke. A key question addressed in the Article is why do calcium-channel blockers reduce stroke risk to a greater extent and β blockers to a lesser extent than expected based on observed effects on blood pressure. Central to the authors’ hypothesis is that usual blood pressure might not be an adequate marker of stroke risk, whereas visit-to-visit variability in SBP might be a more powerful predictor of stroke independent of mean SBP. The authors chose two clinical trial databases for study—the AngloScandinavian Cardiac Outcomes Trial Blood Pressure Lowering Arm (ASCOT-BPLA)7,8 and the Medical Research Council (MRC) trial.9 SBP, DBP, and pulse pressure withinindividual visit-to-visit variability were expressed as the standard deviation (SD) and coefficient of variation of readings taken over multiple follow-up visits. Meticulous and thoughtful analyses were done based on initial fall of blood pressure, average successive variability, and residual SD.6 Key findings are listed in the panel. Rothwell and colleagues6 suggest that, although blood pressure-lowering drugs reduce mean blood pressure, variability of blood pressure during treatment with a specific drug might be a significant predictor of whether or not stroke prevention is successfully achieved. Furthermore, an accompanying Review10 reports that the findings might be generalisable by class of bloodpressure-lowering drug. The brain does not tolerate instability of blood pressure or blood pressure variability well: brain atrophy, subcortical lesions, and cognitive impairment might occur as consequences.11,12 Rothwell and colleagues6 make a coherent argument and provide a rationale that drugs that reduce blood pressure variability might be more beneficial than drugs that do not reduce blood pressure www.thelancet.com/neurology Vol 9 May 2010
Reflection and Reaction
variability, and prerandomisation (or pretreatment) runin assessment to test for variability of blood pressure could be informative.6 β adrenergic receptor blockers, such as atenolol, presumably lower blood pressure by decreasing cardiac output, inhibiting release of renin and the production of angiotensin II, possibly reducing norepinephrine release from sympathetic neurons, and decreasing central vasomotor activity.3 These drugs can be effective in young white patients with hypertension, those with resting tachycardia, angina, or previous myocardial infarction, and as add-on therapy in patients with congestive heart failure.3 However, several β blockers (particularly atenolol) are not ideal treatments for hypertension, because they have a reduced ability to protect against stroke, and might cause weight gain, dyslipidaemia, and impaired glucose control.2 Rothwell and colleagues6 are to be congratulated for bringing forth compelling findings that eventually might set the foundation for a major change in our practice of blood pressure treatment for the prevention of stroke or other cardiovascular diseases. Therefore, clinicians should give careful consideration to use of drugs associated with low variability in blood pressure.7 Although major guidelines previously expressed caution about the use of β blockers in patients with hypertension and relegated them as less suitable initial therapy,13 we now have an additional rationale—variability of blood pressure—as to why these drugs might not significantly reduce stroke risk. Finally, central aortic blood pressure has been proposed as a more accurate reflection of loading conditions of the left ventricular myocardium and coronary and cerebral arteries. The findings of Rothwell and colleagues6 might prove particularly important if the theory of central aortic blood pressure does not pan out or if both can be applied in clinical practice in a complementary manner, especially if the types of blood-pressure-lowering drugs that lower
central aortic pressure and blood pressure variability are from the same class or classes. Philip B Gorelick Center for Stroke Research, Department of Neurology and Rehabilitation, University of Illinois College of Medicine at Chicago, Chicago, IL 60612, USA [email protected] I have received consultancy fees for serving as an adviser on blood pressurelowering therapy for Novartis and Daiichi Sankyo and on the cardiovascular study adjudication committee for Pfizer. I received consultancy fees for serving on the Boehringer Ingelheim PRoFESS steering committee and my institution received fees for my service on a Boehringer Ingelheim speakers’ bureau. 1 2 3 4
5 6
7
8
9 10
11 12
13
Gorelick PB. New horizons for stroke prevention: PROGRESS and HOPE. Lancet Neurol 2002; 1: 149–56. Aiyagari V, Gorelick PB. Management of blood pressure for acute and recurrent stroke. Stroke 2009; 40: 2251–56. Moser M. Clinical Management of Hypertension (7th edn). West Islip, NY, USA: Professional Communications, 2004. Chobanian AV, Bakris GL, Black HR, et al, and the National High Blood Pressure Education Program Coordinating Committee. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. The JNC 7 Report. JAMA 2003; 289: 2560–72. Carlberg B, Samuelsson O, Lindholm LJ. Atenolol in hypertension: is it a wise choice? Lancet 2004; 364: 1684–89. Rothwell PM, Howard SC, Dolan E, et al, on behalf of the ASCOT-BPLA and MRC Trial Investigators. Effects of β blockers and calcium-channel blockers on within-individual variability in blood pressure and risk of stroke. Lancet Neurol 2010; published online March 12. DOI:10.1016/S1474-4422(10)70066-1. Dahlof B, Sever PS, Poulter NR, et al, ASCOT Investigators. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet 2005; 366: 895–906. Poulter NR, Wedel H, Dahlöf B, et al, for the ASCOT investigators. Role of blood pressure and other variables in the differential cardiovascular event rates noted in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA). Lancet 2005; 366: 907–13. MRC Working Party. Medical Research Council trial of treatment of hypertension in older adults: principal results. BMJ 1992; 304: 405–12. Rothwell PM. Limitations of the usual blood pressure hypothesis and importance of variability, instability, and episodic hypertension. Lancet 2010; 375: 938–48. Goldstein IB, Bartzokis G, Guthrie D, Shapiro D. Ambulatory blood pressure and the brain: a 5-year follow-up. Neurology 2005; 64: 1846–52. Zuccala G, Onder G, Pedone C, et al, for the GIFA-ONLUS Study Group. Hypotension and cognitive impairment. Selective association in patients with heart failure. Neurology 2001; 57: 1986–92. Williams B. Evolution of hypertensive disease: a revolution in guidelines. Lancet 2006; 368: 6–8.
Lithium time-to-event trial in amyotrophic lateral sclerosis stops early for futility Clinical trials in amyotrophic lateral sclerosis (ALS) remain stuck in a rut: so many trials, such high expectations, such disappointing results. Since the trials of riluzole 15 years ago,1 no new drug for treatment of ALS has been introduced on to the market. Preclinical www.thelancet.com/neurology Vol 9 May 2010
trials using the only available animal model, the highcopy G93A superoxide dismutase 1 (SOD1) transgenic mouse, clearly have poor predictive value with regard to treatment of human sporadic ALS. Several different factors have contributed to the failure of this model:
Published Online April 6, 2010 DOI:10.1016/S14744422(10)70085-5 See Articles page 481
449