Rapid Responses to:
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blockers in hypertension and cardiovascular disease
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The tolerability of different beta blockers also varies depending on whether or not there is co-existent airflow obstruction
- oscar,m jolobe (6 May 2007)
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Methods matter! Certainty of conclusions are threatened by misuse of confidence intervals.
- Christopher J Cates (7 May 2007)
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Inferiority of atenolol to other beta-blockers is statistically significant
- Ivar Aursnes, Jan-Bjørn Osnes, and Bent Natvig (10 May 2007)
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Atenolol is presumably inferior to other agents
- Zvonko Rumboldt (13 May 2007)
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Role of Beta blockers is still immense in uncomplicated& primary hypertension in West Bengal ,India, & doctors prefer it as first line treatment choice of hypertension in Young up to 45-55 age groups without Diabetes Mellitus
- Professor Pranab Kumar Bhattacharya, Bhattacharya Rupak Bsc(cal), Msc(JU), Islam Sahidul Dipcard, DM(cal) RMO, ICVS, IPGMER, Chatterjee Bhabani Prasad DM(Cardio) Cal Consul Cardiologist, Mukherjee Dipankar DM(cardio) Cal , Asst. Prof, ICVS, IPGMER Kol-20 (22 May 2007)
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Does beta-blocker withdrawal lead to development of atrial fibrillation?
- Roger E Stephenson, Peter Selley (22 November 2007)
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oscar,m jolobe, retired geriatrician manchester medical society, c/o john rylands university library, oxford road, manchester, M13 9PP
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The variability in the efficacy of subclasses of beta adrenergic blocking drugs(beta-blockers) in cardiovascular disease(1) has, as its corollary, the varability in the tolerability of different subclasses of beta blockers in those patients in whom cardiovascular disease co-exists with airflow obstruction. For example, unlike the non-selective beta blocker, propranolol, which causes deterioration in the one second forced expiratory volume(FEV1) when administered to patients with chronic obstructive pulmonary disease(COPD), the cardioselective agent, metoprolol, does not have this adverse effect(2), the tolerability of cardioselective agents in COPD being borne out by an extensive meta- analysis(3). In the comparison between COPD patients(defined as those with irreversible airflow limitation) and asthmatics(defined as having "significant" reversibility), the combination of alpha adrenergic receptor blockade and non-selective beta blockade, exemplified by carvedilol, proved to be better tolerated in COPD patients than in asthmatics(4), although this study did not take into account the fact that the distinction between COPD and asthma may be blurred when using the acute bronchodilator response as a distinguishing feature(5). A robust distinction between COPD and asthma is necessary as it would make it easier for clinicians to "switch" from metoprolol to carvedilol when treating heart failure patients with co-existing COPD, given the fact that the comparison between the two agents, in mild to severe chronic heart failure, reported a significant survival benefit for carvedilol(6) References (1) Ong HT Beta blockers in hyperyension and cardiovascular disease British Medical Journal 2007:334:946-9 (2) van der Woude HJ., Zaagsma J., Postma DJ et al Detrimental effects of Beta-blockers in COPD: A concern for nonselective Beta blockers Chest 2005:127:818-24 (3)Salpeter SR., Ormiston TM., Salpeter EE., Poole PJ., Cates CJ Cardioselective beta-blockers for chronic obstructive pulmonary disease: a meta-analysis Respiratory Medicine 2003:97:1094-1101 (4) Kotlyar E., Keogh AM., Macdonald PS eta l Tolerability of carvedilol in patients with heart failure and concomitant chronic obstructive pulmonary disease or asthma The Journal of Heart and Lung Transplantation 2002:21:1290-95 (5) Chhabra SK Acute bronchodilator response has limited value in differentiating bronchial asthma from COPD Journal of Asthma 2005:42:367-72 (6)Poole-Wilson PA., Swedberg K., Cleland JGF et al Comparison of carvedilol and metoprolol on clinicalm outcomes in patients with chronic heart failure. Results of the Carvedilol Or Metoprolol European Trial(COMET) Lancet 2003:362:7-13 Competing interests: None declared |
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Christopher J Cates, GP Manor View Practice, Bushey, WD23 2NN
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Editor, The data presented in Table 1 of this review actually leave considerable uncertainty about whether atenolol is better or worse than other beta blockers. The confidence intervals for the results on other beta blockers are wide (as fewer patients have been studied), and the test for interaction shows that the Relative Risk comparing atenolol to other beta blockers for stroke is 1.05 (95% CI 0.26 to 4.17), for myocardial infarction 1.22 (0.91 to 1.63) and for total mortality 1.21 (0.95 to 1.14). All of these confidence intervals include the possibility of no difference, and for stroke the results are compatible with atenolol being four times better or four times worse than other beta blockers! It is very misleading to draw conclusions based on whether statistical significance is achieved with either treatment alone.[1] [1] Altman DG, Bland JM. Statistics Notes: Interaction revisited: the difference between two estimates. BMJ. 2003 January 25, 2003;326(7382):219 Competing interests: None declared |
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Ivar Aursnes, professor Department of Pharmacotherapeutics, University of Oslo, Jan-Bjørn Osnes, and Bent Natvig
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Ever since the mortality among metoprolol treated hypertensive patients was found to be lower than among similar patients given atenolol [1], we have suspected atenolol to be inferior in effect to other beta- adrenergic blockers, especially for the prevention of coronary disease events. Those patients were admittedly not randomized to the drugs and the difference was not statistically significant. We noticed that atenolol in the review by Ong [2] has gained an inferior position compared with other beta-blockers, but the author seems to be hesitant to reach a final verdict due to lack of statistical significance. We have recently re-analysed and published [3] the data that were presented in the review by Carlberg et al [4], to which Ong refers. Briefly, both atenolol and non-atenolol beta-adrenergic blockers were tested in some trials against other antihypertensive drugs and in other trials against placebo. For coronary disease prevention, the two sets of trials both indicate inferiority of atenolol, with none of the two summarised effects showing statistical significance. The two approaches can, however, be combined using a Bayesian statistical approach [3]. Our calculations showed 13% lower risk (risk ratio 0.87) of myocardial infarction among hypertensive patients taking non-atenolol beta-adrenergic blockers than among hypertensive patients taking atenolol. The 90% credibility interval ranged from 0.75 to 0.99, thereby indicating one- sided statistical significance below the 5% level. The probability of at least 10% lower risk (risk ratio <0.90), which could be considered to be of clinical interest, was 0.69. We believe the one-sided approach is justified on the background of other signs of inferiority of atenolol to other beta-blockers mentioned by Ong, plus the reported comparison with metoprolol [1]. Moreover, pre-clinical investigations of atenolol point in the same direction. The lack of lipid solubility of atenolol and thus the low distribution to the brain most likely prevents beneficial effect components as exerted by most other beta-adrenergic blockers in the CNS. So far only reported in an abstract, the vagal tone in dogs following medication with atenolol did not increase compared with metoprolol. This made the atenolol treated dogs more vulnerable for ventricular fibrillation provoking stimuli [5]. It follows that atenolol is not representative of the beta-adrenergic blocker class of drugs as a whole and is thus not a suitable drug for comparisons with other antihypertensive drugs in terms of effect. The non- atenolol beta-adrenergic blockers should in our opinion continue to be fundamental in antihypertensive drug treatments. 1 The Steering Committee of the HAPPHY Trial. MAPHY and the two arms of HAPPHY. JAMA 1989;262:3273-4. 2 Ong HT. Beta-blockers in hypertension and cardiovascular disease. BMJ 2007;334:946-9. (5 May.) 3 Aursnes I, Osnes JB, Tvete IF, Gaasemyr J, Natvig B. Is atenolol different from other adrenergic blockers? BMC Clinical Pharmacology 2007. www.biomedcentral.com/1472-6904/7/4 (accessed 10 May 2007). 4 Carlberg B, Samuelsson O, Lindholm LH. Atenolol in hypertension: is it a wise choice? Lancet 2004;364:1684-89. 5 Åblad B, Bjurö T, Björkman J-A, Edström T, Olsson G. Role of central nervous beta-adrenoceptors in the prevention of ventricular fibrillation through augmentation of cardiac vagal tone. J Am Coll Cardiol 1991;17:1A.65. Competing interests: None declared |
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Zvonko Rumboldt, Professor of Internal Medicine & Clinical Pharmacology Split University School of Medicine, 21000 Split, Šoltanska 2, Croatia
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The balanced report of Ong is welcome (1). Atenolol is presumably inferior to other beta-adrenergic blockers, as already shown in the review and in the quoted references. The difference may be due to its low lipophilicity with minimal CNS effects, to its poor efficacy on the regression of left ventricular hypertrophy or to its marginal impact on endothelial dysfunction. In addition, we have recently shown (2) that atenolol has negligible or even adverse effect on platelet aggregability, opposite to propranolol (compared were the circulating platelet aggregates). As an additional hint I suggest the intuitive (?) selection of atenolol as an active comparator in the large, industry sponsored studies such as LIFE or ASCOT. It seems to me that a low-dosed thiazide diuretic or another beta-blocker, such as bisoprolol, carvedilol, metoprolol or nebivolol, would be a better choice for a fair comparison. References 1. Ong HT. Beta blockers in hypertension and cardiovascular disease. BMJ 2007;334:946-9. 2. Punda A, Poliæ S, Rumboldt Z, Bagatin J, Markoviæ V, Lukin A. Effects of atenolol and propranolol on platelet aggregation in moderate essential hypertension: a randomizes crossover trial. Croat Med J 2005;46:219-24. Competing interests: None declared |
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Professor Pranab Kumar Bhattacharya, Professor, Pathology, Incharge of Unit,; Blood Bank &VCTC, Ctogenetics, Ronald Ross Malaria clinic Institute of Post Graduate Medical Education & Research(IPGMER), 244A AJC Bose Road, Kolkata-20, W.B, Bhattacharya Rupak Bsc(cal), Msc(JU), Islam Sahidul Dipcard, DM(cal) RMO, ICVS, IPGMER, Chatterjee Bhabani Prasad DM(Cardio) Cal Consul Cardiologist, Mukherjee Dipankar DM(cardio) Cal , Asst. Prof, ICVS, IPGMER Kol-20
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In the West Bengal State of India the distribution of major causes of hospitalization in four medical colleges showed that the highest admission rate is for cerebrovascular and cardiovascular causes (15.6%), and the major causes of mortality in kolkata based Medical colleges is Cerebrovascular and Cardiovascular Diseases (33.12%). In the districts of West Bengal the incidence of Cerebrovascular/ Cardiovascular disease admission is 11.13% and mortality is 35%(1). As such, mortality and morbidity scenario of the state is different in metropolis and in districts of West Bengal and has changed a lot from increased incidence of Cerebrovascular (Stroke) and Cardiovascular (AMI and Heart Failure). Hypertension is the leading causes 36% of incidence of stroke and 21% increase of Coronary heart disease in India(2). So goal of therapy of Hypertension must be to reduce incidence of stroke, to reduce incidence of AMI, Heart failure and Left Ventricular Hypertrophy from hypertension, which is also an isolated risk factors of SCD. In West Bengal large numbers of Population above age range of 47 are receiving antihypertensive treatment and in mild to moderate hypertension of BP ranges (144—147 +- 2/97.1+-1.5mmHg) the choice of drug therapy by the cardiologist and General Practitioners are Beta Blockers, mainly atenolol with or without low dose combination of Hydrochlorothiazide and in Type 2 Diabetes Mellitus having Hypertension is treated by ACE inhibitors or ARBs. All people with a present BP>140/90 mmHg or a high normal BP 135-139/85 -89 or a family history of hypertension must follow modification of advice to reduce their BP and CVD risk. Blood Pressure threshold for pharmacotherapy SP 140-159 mmHg and Diastolic 90-99 mmHg having total CVD risk>20% or have diabetes or have target organ damage should be considered for drug therapy. People with persistent elevation of SP>160 mmHg and or diastolic >100mm Hg one at Sufficiently high CVD risk on the basis of BP alone must require drug therapy to reduce BP. People with Grade I hypertension but without CVD, DM, Target organ damage and total CVD risk<20% may be treated with life style modification but their BP and CVD risk has to be re-assessed annually. People with Myocardial Infraction, Stroke, TIA or people with Established Renal disease or with DM will benefit from BP lowering 130/80 mmHg. However to achieve the level of BP control at 130/80 mmHg through out months, years is very difficult job in West Bengal set up, as we the authors know. And those people who are at high risk for CVD, a good or optimal control of BP if all treated hypertensive maintain their BP at 140/80 mmHg The British Hypertension Society AB/CD algorithm was designed to improve Blood Pressure control. It incorporated all classes of hypertensive. The theory underlying AB/CD is that Hypertension can be classified as ‘ High Rennin “ or Low Rennin” and is therefore best treated initially with one of two categories of antihypertensives drugs : Those that Inhibit Rennin- Angiotensin system ACE inhibitors or ARBS (A) or Beta Blockers(B) and That do not (C) or Thiazide/ Thiazide like Diuretics(D). People who are younger aged <55 years and white race tend to have higher rennin concentration than older people than aged 55 years or Black people like Indians and Asians. A or B drugs are therefore generally more effective as initial blood pressure lowering treatment in younger patients and in white race than C or D drugs. However C or D drugs are more effective for the older people and Black People. In AB/CD algorithm Beta blockers showed some contraindications however. These are because several trials including the largest randomized comparison of Beta blockers/thaizide against Calcium Channel Blockers(CCB)/ACE in Primary prevention of coronary Vascular disease (ASCOT_BPLA-a Company Sponsored Trial?)have revealed increased risk of Developing DM in people treated with Beta Blockers especially when combined with thiazide/ thiazide like diuretics(4&5). In ASCOT BPLA the incidence of new diabetes was 1.6/100 patients year in the beta blockers group when compared to 1.1/100 patients years in CCB/ACE arm group Beta blockers mostly “atenolol” are used randomly by the cardiologists as first line of therapy in the treatment of primary hypertension in West Bengal. But a meta-analysis published in the leading journal "The Lancet" showed that use of Beta blockers is associated with high risk of Strokes than any other antihypertensive(3). But the conclusion is probably giving a wrong message particularly while treating in younger patients with uncomplicated hypertension as the authors consider. In younger and older patients the mechanism of development of hypertension is different. The Framingham study group(4) showed that over a 10 year period diastolic hypertension that arose in younger patients was linked to high body mass index (BMI) and raised peripheral resistance while in elderly patients isolated systolic hypertension arise de-novo mostly and is closely related to arterial stiffness. Younger overweight hypertensives have a high sympathetic drive and cardiac output- a situation that can be treate wellwell by B blockers. The Question remains which should be target of therapy for treatment of Hypertension to prevent the complication & death--Angiotensin Renin pathway or Aldesterone path way? LVH is the most important predictor of Cardiovascular morbidity and Mortality in Hypertensive patients as well as in General Population and it is influenced by many variables such as obesity, dietary Habits, Pressure overloads and also by genetic Polymorphism. It was demonstrated that several vasoactive substances such as Angiotensin II and also aldosterone acting as growth factors associated with development of concentric LVH in Hypertension Five Studies on effects of Beta Blockers treatment on mortality like CIBS I &II, COPERNICUS, MERIT-HF and BEST and US Carvedelol Trial were included in meta analysis showed a pooled 2134 Women and 7885 men and the study showed beneficial reductions in all case mortality with Beta Blockers in men and women, the use of ACE inhibitors in Black and white patients. However that Study concluded that women with asymptomatic LV dysfunction did not have reduced mortality with ACE inhibitors only.(6) RALES study demonstrated combination of Aldesterone and ACE inhibitors can Reduce the mortality and Morbidity from Cardiac Failure and acts as direct Cardio protective In patients with raised BP and symptomatic angina, Beta Blockers is no doubt preferred treatment of choice as per authors also. Beta Blockers are indicated with hypertension & CHD(unless there is contraindications like asthma, COPD, heart block in the following conditions like control of symptoms of myocardial ischemia, CVD protectors following AMI, reduction of BP to target< 130/80mmHG. In a meta analysis of Beta blockers following AMI, there was evidence of Significant reduction of all cases mortality, cardiovascular death and particularly SCD as well as non fatal re- infraction- which should be the goal of therapy.(7) The absolute benefit of Beta Blockers are greatest in older people(>60 Years) and in people with increased risk of re- infraction & death from LVH, LV dysfunction or arrhythmia or both. In the market of West Bengal many Beta Blockers are marketed and of which mostly prescribed drug is “Atenolol” both by cardiologists as well as by General Practitioners , Metoprolol ( very little & occasionally prescribed) , Carvedilol. Which Beta blockers are mostly useful is still uncertain. Theoretically Metoprolol is Beta-1 selective and should be more effective. The First author has also taken Metoprolol for his hypertension and concentric hypertensive LVH for the past 9 years. The problem the first authors is that he feels insomnia, occasional night mare, fatigue and loss of Libido. Bisoprolol is also Beta-1 selective when Carvedilol is beta- 1&2 & alpha-1 selective with antioxidant property in addition. The consensus of three cardiologists in this article is that Atenolol is the drug of choice of treatment in uncomplicated hypertension in young when Metoprolol in the hypertension with increased CVD Risk>20% and and Carvedilol if there is heart failure associated. References 1) Health on the March 2005-06 of state Bureau of Health Intellegence, Directorate of Health Services, Government of West Bengal, Swasthya Bhavan, GN-29, Sector V Salt Lake, Kolkata -91 , December 2006, P-191-94 2) Bhattacharya Pranab Kumar. Bose Debdas, Bhattacharya Rupak, Islam sahidul, Bhattacharya Palash’ Hypertension & Moderate restriction of Salt Intake in Food is beneficial as preventive measure to normo tensive as well as in Hypertensive in West Bengal State of India” Rapid Response Published for Nancy. R cook BMJ 2007;334;885 Http:/www.bmj.com.cigi/eletters/334/7599/885 Page 8-13 3) Lindholm.L.H, Carlberg.B, Samulsion. O ‘ Should B blockers remain first choice in treatment of primary hypertension? –A meta analysis Lancet 2005;366;1545-57 4) Daholf.B, Devereu XRb, Kjeldsen SE et al “ Cardiovascular morbidity and Mortality in the losartan intervention for end point reduction in hypertension(LIFE)- a randomized trial against atenolol :Lancet 2002;359;995-1003 5) Daholf B, Sever PS, Poulter NR etal for the ASCOT investigators: prevention of Cardiovascular events with an antihypertensive regimen amlodipine adding Perindopril as required versus atenolol adding Bendroflumethazide as required in Anglo- Scandinavian Cardiac Out comes Trial Blood Pressure Lowering Arm(ASCOT_BPLA): a multicenter randomized controlled d Trial :The Lancet 2005;366;895-906 6) Paul G Shekella, Michel W Rich, Sally. C Mohan Et al “ Efficacy of ACE inhibiotors and Beta Blockers in the Management of Lt. Ventricular Systolic dysfunction According to Race, Gender, diabetic Status- A meta Analysis of Mazor Clinical Trials” Journal of The American College of Cardiology 41:N9:1529-38;2003 Acknowledgement-: Authors gratefully acknowledge Mr. Ritwik Bhattacharya of Purbapalli, Sodepur, 24 Parganas(north) Kolkata-110., Miss Upasana Bhattacharya of Delhi Public School Rubipark ,Kolkata, Miss Aindrila Mukherjee of Swamizi Nagar south Habra, 24 parganas (North).W.B Authors *1) Professor Pranab Kumar Bhattacharya MD(cal), FIC Path(Ind)
**2) Mr. Rupak Bhattacharya Bsc(cal), Msc(JU)
*** 3) Dr. Sahidul Islam MD(cal), Dip Card(Cal), DM(cal)
4) Dr. Bhabani Prasad Chatterjee MD(cal), DM(cal)
5) Dr. Dipankar Mukherjee MD(cal), DM(cal)
Competing interests: None declared |
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Roger E Stephenson, General Practitioner Bow Medical Centre, Fair Park, Bow, CREDITON EX17 6EY, Peter Selley
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Sir, Ong (1) presents data suggesting that atenolol is inferior to other beta-blockers in older hypertensive patients. NICE guidance tells us to “revise treatment according to the treatment algorithm” in such patients, which includes withdrawing beta-blockers (2). But is this safe? Since the NICE guidance we have withdrawn atenolol from approximately 20-25 patients treated for hypertension (list size approx 2500). Of these, three have developed atrial fibrillation within a maximum of two months of stopping. One of these three developed atrial fibrillation five months after halving her dose. A fourth patient who stopped his beta-blocker before the guidance, developed atrial fibrillation nine months after cessation. Taken together with the letter from Christopher Cates (3) this begins to cast doubt on recommendations 9 (revise treatment) and 11 (step down gradually) of NICE’s latest hypertension guidance. A Medline search reveals no published connection between withdrawal of beta blockers and atrial fibrillation, so we would be interested to hear whether anyone else in primary care has had similar experiences. Have cardiologists been inundated with referrals for cardioversion? Roger Stephenson, General Practitioner Bow Medical Centre, Fair Park, Bow, CREDITON, Devon EX17 6EY Roger.Stephenson@gp-L83640.nhs.uk Peter Selley, Retired General Practitioner Clínica Misional "Nuestra Señora de Guadalupe" Zamora-Chinchipe, Ecuador peter.selley@which.net Competing Interests: None 1) Ong HT. blockers in hypertension and cardiovascular disease. BMJ 2007;334:946-9. (5 May.) 2) National Collaborating Centre for Chronic Conditions. Hypertension: management of hypertension in adults in primary care: partial update. London: Royal College of Physicians, 2006. www.nice.org.uk/CG034guidance 3) Cates, C. J (2007). Misuse of confidence intervals threatens conclusions. BMJ 334: 1020-1020 Competing interests: None declared |
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