- Email: [email protected]
β blockers for the treatment of primary hypertension
By lumping together all randomised hypertension trials involving blockers, Lars Lindholm and colleagues1 have arrived at misleading conclusions. The lumping process ignores the fact that the development of hypertension in younger and older patients involves quite different physiological processes calling for different therapeutic considerations. The Framingham Study group2 showed that, over a 10-year period, diastolic hypertension that arose in younger patients was closely linked to a high body-mass index (BMI) and raised peripheral resistance. By contrast, in elderly patients, isolated systolic hypertension arose de novo (mostly), and not from burned-out diastolic hypertension, and was closely linked to increased arterial stiffness. Younger overweight hypertensive patients, particularly with diabetes, have a high sympathetic drive and cardiac output, a situation well suited to first-line 1 blockade. Older people with hypertension would be best suited to first-line agents that improve vascular compliance (ie, not atenolol or propranolol). In fact the essence of the -blocker story is enshrined in three classic studies: the MRC-1,3 MRCelderly,4 and UKPDS5 studies. The MRC-1 and UKPDS studies involved younger patients, and myocardial infarction was the main cardiovascular endpoint (about three times more common than stroke). In the MRC-1 study,3 the mean age was 51 years, mean BMI 27 kg/m2, and mean pulse-pressure 63 mm Hg; 25–30% were smokers. Propranolol, but not diuretics, reduced the risk of myocardial infarction by 13% (which increased to a significant 18% when silent infarctions were included in a subsequent subanalysis) compared with placebo; in non-smokers the reduction was 33%. The UKPDS study5 involved hypertensive patients with diabetes, mean age 56 years, mean BMI 29 kg/m2, and mean pulsepressure 65 mm Hg. After 9 years’ follow-up, the trends in all seven www.thelancet.com Vol 367 January 21, 2006
primary endpoints favoured atenolol over captopril, indicating that the significant cardiovascular benefit of tight blood pressure control (atenolol plus captopril) over light control (surrogate placebo) was due mainly to atenolol (despite induced increases in glycosylated haemoglobin). The MRC-elderly study4 involved patients of mean age 70 years and pulse-pressure 94 mm Hg, and compared placebo, first-line diuretic with or without atenolol, and first-line atenolol with or without diuretic. The effects of first-line atenolol did not differ from placebo, by contrast with first-line diuretic, which reduced stroke by 31% and myocardial infarction by 44%. Thus I disagree that blockers no longer have a role in the treatment of hypertension, provided these agents are prescribed sensibly—ie, as first-line treatment in younger patients and as second-line in elderly patients— avoiding 2 blockade if possible. I declare that I have no conflict of interest.
John M Cruickshank [email protected] 42 Harefield, Long Melford CO10 9DE, UK 1
2
3
4
5
Lindholm LH, Carlberg B, Samuelsson O. Should blockers remain first choice in the treatment of primary hypertension? A metaanalysis. Lancet 2005; 366: 1545–53. Franklin SS, Pio JR, Wong ND, et al. Predictors of new-onset diastolic and systolic hypertension: the Framingham Heart Study. Circulation 2005; 111: 1121–27. MRC Working Party. MRC trial of treatment of mild hypertension: principal results. BMJ 1985; 291: 97–104. MRC Working Party. Medical Research Council Trial of treatment of hypertension in older adults: principal results. BMJ 1992; 304: 405–12. UK Prospective Diabetes Study Group. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. BMJ 1998; 317: 713–20.
I was disappointed to see the cover of the Oct 29 issue carry the misleading statement “ blockers should not remain first choice in the treatment of primary hypertension”, based on the paper by Lars Lindholm and colleagues.1 Three major trials have
attempted to show the benefit of non-blocker-based treatment and all have been confounded by differences in blood pressure between regimens.2–4 Lindholm and colleagues’ statement “-blockers lower blood pressure to the same extent as other antihypertensives” is well supported by data. However, since their analysis “cannot be controlled for attained blood pressure”, it does little to further our understanding, given the extent of evidence that equivalent blood pressure reduction has not been achieved in many well done, largescale trials (with the notable exception of LIFE5). The unequivocal evidence is that what matters in terms of preventing stroke and heart attack is having good blood pressure control. Individuals vary in their response to treatment and this cannot be predicted in any useful clinical sense for any given agent. Primary hypertension does not equate to uncomplicated hypertension. Emphasis should be given to the tailoring of treatment to the individual. There are many compelling reasons to use blockers in some individuals. When there are not, an inexpensive diuretic has much to offer as first choice (http://www.nhlbi.nih. gov/guidelines/hypertension/index.ht m). The real decision point for most is then the second agent, although adding the diuretic as second line is equally acceptable to many (either approach is endorsed by the European Society of Hypertension, http://www. guidelines.gov/summary/summary.as px?doc_id=4765&nbr=3445). There is understandable reluctance to combine diuretics and blockers, for the reasons expressed by Lindholm and colleagues and the British Hypertension Society (http://www.bh soc.org), but it should at least be acknowledged that the evidence remains equivocal. Patients with good blood pressure control and freedom from side-effects on blockers should not be made to feel at risk: they are not. They also serve to show the
Rights were not granted to include this image in electronic media. Please refer to the printed journal
209
Science Photo Library
Correspondence
Correspondence
efficacy and tolerability of this important class of drugs for many. I declare that I have no conflict of interest.
Stephen G Ball [email protected] Academic Unit of Cardiovascular Medicine, G Floor, Jubilee Building, Yorkshire Heart Centre, Leeds General Infirmary, Leeds LS1 3EX, UK 1
2
3
4
5
Lindholm LH, Carlberg B, Samulesson O. Should blockers remain first choice in the treatment of primary hypertension? A metaanalysis. Lancet 2005; 366: 1545–53. ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic. JAMA 2002; 288: 2981–97. Julius S, Kjeldsen SE, Weber M, et al, for the VALUE trial group. Outcomes in hypertensive patients at high cardiovascular risk treated with regimes based on valsartan or amlodipine: the VALUE randomised trial. Lancet 2004; 363: 2002–31. Dahlöf B, Sever PS, Poulter NR, et al, for the ASCOT Investigators. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the AngloScandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet 2005; 366: 895–906. Dahlöf B, Devereux RB, Kjeldsen SE, et al, for the LIFE study group. Cardiovascular morbidity and mortality in the losartan intervention for endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002; 359: 995–1003.
Authors’ reply Nadia Khan and Finlay McAlister argue that we should have included the CAPPP,1 AASK,2 and VA3 trials in our meta-analysis. The main reason for excluding CAPPP1 was that there was no information on the use of blockers. There were also problems in terms of unbalanced randomisation, oncedaily administration of captopril, etc. Hence we could not extrapolate the use of blockers from other trials to CAPPP as Khan and McAlister suggest. AASK2 included patients with renal insufficiency and not patients with primary hypertension. Moreover, the outcome data for myocardial infarction and stroke were not given separately. The seven clinical events in the small VA study3 we excluded were poorly defined and included suspected cases. Hence, we followed our prede210
fined selection strategy. Khan and McAlister also argue that there is heterogeneity when the effect of all blockers is compared with that of other antihypertensive drugs (figure 1A of our paper). We agree, and this is why we split the data into nonatenolol, mixed, and atenolol trials (figures 1B–D). Along with John Cruickshank and Stephen Ball, Khan and McAlister stress the importance of individualised antihypertensive treatment and argue that there might be good reasons to use blockers in some patients. We fully agree, as stated in our Discussion. However, we could not analyse the outcomes of the included trials for different age-groups, since the studies did not report such information in a uniform manner, mixed trials were only done in older patients, etc. To use blockers in young hypertensive patients, as the correspondents suggest, often in combination with diuretics, might not be a wise choice given the high risk of developing diabetes with that drug combination. Cruickshank states that, in a subanalysis of the MRC trial, propranolol significantly reduced the risk of myocardial infarction by 18%. However, the difference between propranolol and placebo was only 13% (not significant) in the original trial and one should be very careful indeed before accepting post-hoc analyses. Furthermore, such analyses showed that, at each level of blood pressure control, the stroke rate was lower in the thiazide group than in either the propranolol group or the placebo group.4 Ball points out that equivalent (brachial) blood pressure reduction has not been attained in several of the later trials. We agree, but as we discussed in our paper, the suboptimum effect of blockers on central blood pressure might be one of the main reasons for the poor outcome of this class of drugs in primary hypertension. This possibility was further emphasised by new data from the ASCOT CAFÉ study,
presented at the American Heart Association meeting in November, 2005. Finally, we disagree with Cruickshank, Khan, and McAlister about Gareth Beevers’s Comment5 on our paper, which we found well balanced, worth reading, and, in fact, in line with much of what has been said above. We declare that we have no conflict of interest other than that stated in the original paper.
*Lars Hjalmar Lindholm, Bo Carlberg, Ola Samuelsson [email protected] Department of Public Health and Clinical Medicine, Umeå University Hospital, SE 901 85 Umeå, Sweden (LHL, BC); and Department of Nephrology, Sahlgrenska University Hospital, Göteborg, Sweden (OS) 1
2
3
4
5
Hansson L, Lindholm LH, Niskanen L, et al. Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial. Lancet 1999; 353: 611–16. Wright JT Jr, Bakris G, Greene T, et al, for the African American Study of Kidney Disease and Hypertension Study Group. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial. JAMA 2002; 288: 2421–23. Veterans Administration Cooperative Study Group on Antihypertensive Agents. Comparison of propranolol and hydrochlorothiazide for the initial treatment of hypertension, II—results of long-term therapy. JAMA 1982; 248: 2004–11. Miall WE, Greenberg G, Brennan P. Further results of the MRC treatment trial for mild hypertension. Nephron 1987; 47 (suppl 1): 111–14. Beevers DG. The end of blockers for uncomplicated hypertension? Lancet 2005; 366: 1510–12.
Department of Error Biederman J, Faraone SV. Attention-deficit hyperactivity disorder. Lancet 2005; 366: 237–48—In this Seminar (July 16), the table 2 footnote should read: “*LOD=logarithm of the odds (to the base 10). Study 1=US study of 270 sib-pairs.58 Study 2=Dutch study of 164 sib-pairs.59 Study 3=Colombian study of 14 three-generation pedigrees.60”; the last sentence in the second paragraph on p 240 should read: “Several studies assessed the association between the gene and ADHD in people and a meta-analysis of these studies recorded an odds ratio of 1·19.56“; the year of publication in reference 58 should be 2003; and the authorship in reference 152 should be Poulton A, Cowell CT.
www.thelancet.com Vol 367 January 21, 2006
primary endpoints favoured atenolol over captopril, indicating that the significant cardiovascular benefit of tight blood pressure control (atenolol plus captopril) over light control (surrogate placebo) was due mainly to atenolol (despite induced increases in glycosylated haemoglobin). The MRC-elderly study4 involved patients of mean age 70 years and pulse-pressure 94 mm Hg, and compared placebo, first-line diuretic with or without atenolol, and first-line atenolol with or without diuretic. The effects of first-line atenolol did not differ from placebo, by contrast with first-line diuretic, which reduced stroke by 31% and myocardial infarction by 44%. Thus I disagree that blockers no longer have a role in the treatment of hypertension, provided these agents are prescribed sensibly—ie, as first-line treatment in younger patients and as second-line in elderly patients— avoiding 2 blockade if possible. I declare that I have no conflict of interest.
John M Cruickshank [email protected] 42 Harefield, Long Melford CO10 9DE, UK 1
2
3
4
5
Lindholm LH, Carlberg B, Samuelsson O. Should blockers remain first choice in the treatment of primary hypertension? A metaanalysis. Lancet 2005; 366: 1545–53. Franklin SS, Pio JR, Wong ND, et al. Predictors of new-onset diastolic and systolic hypertension: the Framingham Heart Study. Circulation 2005; 111: 1121–27. MRC Working Party. MRC trial of treatment of mild hypertension: principal results. BMJ 1985; 291: 97–104. MRC Working Party. Medical Research Council Trial of treatment of hypertension in older adults: principal results. BMJ 1992; 304: 405–12. UK Prospective Diabetes Study Group. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. BMJ 1998; 317: 713–20.
I was disappointed to see the cover of the Oct 29 issue carry the misleading statement “ blockers should not remain first choice in the treatment of primary hypertension”, based on the paper by Lars Lindholm and colleagues.1 Three major trials have
attempted to show the benefit of non-blocker-based treatment and all have been confounded by differences in blood pressure between regimens.2–4 Lindholm and colleagues’ statement “-blockers lower blood pressure to the same extent as other antihypertensives” is well supported by data. However, since their analysis “cannot be controlled for attained blood pressure”, it does little to further our understanding, given the extent of evidence that equivalent blood pressure reduction has not been achieved in many well done, largescale trials (with the notable exception of LIFE5). The unequivocal evidence is that what matters in terms of preventing stroke and heart attack is having good blood pressure control. Individuals vary in their response to treatment and this cannot be predicted in any useful clinical sense for any given agent. Primary hypertension does not equate to uncomplicated hypertension. Emphasis should be given to the tailoring of treatment to the individual. There are many compelling reasons to use blockers in some individuals. When there are not, an inexpensive diuretic has much to offer as first choice (http://www.nhlbi.nih. gov/guidelines/hypertension/index.ht m). The real decision point for most is then the second agent, although adding the diuretic as second line is equally acceptable to many (either approach is endorsed by the European Society of Hypertension, http://www. guidelines.gov/summary/summary.as px?doc_id=4765&nbr=3445). There is understandable reluctance to combine diuretics and blockers, for the reasons expressed by Lindholm and colleagues and the British Hypertension Society (http://www.bh soc.org), but it should at least be acknowledged that the evidence remains equivocal. Patients with good blood pressure control and freedom from side-effects on blockers should not be made to feel at risk: they are not. They also serve to show the
Rights were not granted to include this image in electronic media. Please refer to the printed journal
209
Science Photo Library
Correspondence
Correspondence
efficacy and tolerability of this important class of drugs for many. I declare that I have no conflict of interest.
Stephen G Ball [email protected] Academic Unit of Cardiovascular Medicine, G Floor, Jubilee Building, Yorkshire Heart Centre, Leeds General Infirmary, Leeds LS1 3EX, UK 1
2
3
4
5
Lindholm LH, Carlberg B, Samulesson O. Should blockers remain first choice in the treatment of primary hypertension? A metaanalysis. Lancet 2005; 366: 1545–53. ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic. JAMA 2002; 288: 2981–97. Julius S, Kjeldsen SE, Weber M, et al, for the VALUE trial group. Outcomes in hypertensive patients at high cardiovascular risk treated with regimes based on valsartan or amlodipine: the VALUE randomised trial. Lancet 2004; 363: 2002–31. Dahlöf B, Sever PS, Poulter NR, et al, for the ASCOT Investigators. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the AngloScandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet 2005; 366: 895–906. Dahlöf B, Devereux RB, Kjeldsen SE, et al, for the LIFE study group. Cardiovascular morbidity and mortality in the losartan intervention for endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002; 359: 995–1003.
Authors’ reply Nadia Khan and Finlay McAlister argue that we should have included the CAPPP,1 AASK,2 and VA3 trials in our meta-analysis. The main reason for excluding CAPPP1 was that there was no information on the use of blockers. There were also problems in terms of unbalanced randomisation, oncedaily administration of captopril, etc. Hence we could not extrapolate the use of blockers from other trials to CAPPP as Khan and McAlister suggest. AASK2 included patients with renal insufficiency and not patients with primary hypertension. Moreover, the outcome data for myocardial infarction and stroke were not given separately. The seven clinical events in the small VA study3 we excluded were poorly defined and included suspected cases. Hence, we followed our prede210
fined selection strategy. Khan and McAlister also argue that there is heterogeneity when the effect of all blockers is compared with that of other antihypertensive drugs (figure 1A of our paper). We agree, and this is why we split the data into nonatenolol, mixed, and atenolol trials (figures 1B–D). Along with John Cruickshank and Stephen Ball, Khan and McAlister stress the importance of individualised antihypertensive treatment and argue that there might be good reasons to use blockers in some patients. We fully agree, as stated in our Discussion. However, we could not analyse the outcomes of the included trials for different age-groups, since the studies did not report such information in a uniform manner, mixed trials were only done in older patients, etc. To use blockers in young hypertensive patients, as the correspondents suggest, often in combination with diuretics, might not be a wise choice given the high risk of developing diabetes with that drug combination. Cruickshank states that, in a subanalysis of the MRC trial, propranolol significantly reduced the risk of myocardial infarction by 18%. However, the difference between propranolol and placebo was only 13% (not significant) in the original trial and one should be very careful indeed before accepting post-hoc analyses. Furthermore, such analyses showed that, at each level of blood pressure control, the stroke rate was lower in the thiazide group than in either the propranolol group or the placebo group.4 Ball points out that equivalent (brachial) blood pressure reduction has not been attained in several of the later trials. We agree, but as we discussed in our paper, the suboptimum effect of blockers on central blood pressure might be one of the main reasons for the poor outcome of this class of drugs in primary hypertension. This possibility was further emphasised by new data from the ASCOT CAFÉ study,
presented at the American Heart Association meeting in November, 2005. Finally, we disagree with Cruickshank, Khan, and McAlister about Gareth Beevers’s Comment5 on our paper, which we found well balanced, worth reading, and, in fact, in line with much of what has been said above. We declare that we have no conflict of interest other than that stated in the original paper.
*Lars Hjalmar Lindholm, Bo Carlberg, Ola Samuelsson [email protected] Department of Public Health and Clinical Medicine, Umeå University Hospital, SE 901 85 Umeå, Sweden (LHL, BC); and Department of Nephrology, Sahlgrenska University Hospital, Göteborg, Sweden (OS) 1
2
3
4
5
Hansson L, Lindholm LH, Niskanen L, et al. Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial. Lancet 1999; 353: 611–16. Wright JT Jr, Bakris G, Greene T, et al, for the African American Study of Kidney Disease and Hypertension Study Group. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial. JAMA 2002; 288: 2421–23. Veterans Administration Cooperative Study Group on Antihypertensive Agents. Comparison of propranolol and hydrochlorothiazide for the initial treatment of hypertension, II—results of long-term therapy. JAMA 1982; 248: 2004–11. Miall WE, Greenberg G, Brennan P. Further results of the MRC treatment trial for mild hypertension. Nephron 1987; 47 (suppl 1): 111–14. Beevers DG. The end of blockers for uncomplicated hypertension? Lancet 2005; 366: 1510–12.
Department of Error Biederman J, Faraone SV. Attention-deficit hyperactivity disorder. Lancet 2005; 366: 237–48—In this Seminar (July 16), the table 2 footnote should read: “*LOD=logarithm of the odds (to the base 10). Study 1=US study of 270 sib-pairs.58 Study 2=Dutch study of 164 sib-pairs.59 Study 3=Colombian study of 14 three-generation pedigrees.60”; the last sentence in the second paragraph on p 240 should read: “Several studies assessed the association between the gene and ADHD in people and a meta-analysis of these studies recorded an odds ratio of 1·19.56“; the year of publication in reference 58 should be 2003; and the authorship in reference 152 should be Poulton A, Cowell CT.
www.thelancet.com Vol 367 January 21, 2006