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Electronic letters to:
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Electronic letters published:
![[Read eLetter]](/icons/misc/sectionDOWN.gif){kind=icon}
Response to Hoffman and Siebenhofer
Discrepancies and comments: Is recalculation required?
Re-re-examining the efficacy of ß-blockers for hypertension?
“CIRCUMSTANTIAL HYPERTENSION” – CAN WE CONSIDER IT AS A SEPARATE ENTITY
Beta-blockers in hypertension; still suboptimal documentation in young patients.
The young do well on Beta Blockers
Beta blockers are used excessively in developing countries
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Finlay A McAlister University of Alberta
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Finlay.McAlister{at}ualberta.ca Finlay A McAlister
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Dr. Hoffman asserts that the conclusions in our meta-analysis were incorrect as the random effects confidence intervals for figures 1A (B- blocker vs. placebo in trials enrolling younger patients) and 2B (B- blocker vs. other antihypertensives in trials enrolling older patients) appeared to incorporate 1 when they re-ran the analyses on RevMan software. However, unlike Dr. Hoffman, we conducted our random effects analyses using a software program that does not round off at two decimal places. Thus, in both random and fixed effects modeling, while the confidence intervals do approach 1 in neither case do they incorporate 1. The summary effect estimate in figure 1A (B-blocker vs placebo in trials enrolling younger patients) employing the random effects model is 0.862 with 95% CI 0.746 to 0.996 and a p value of 0.044 - this clearly supports the interpretation stated in our paper that b-blockers are more efficacious than placebo in these younger patients. Similarily, the summary effect estimate for figure 2B (B-blocker vs other antihypertensives in trials enrolling older patients) using the random effects model and not rounding off at two decimal places is 1.066 with 95% CI 1.001 to 1.135 and p value of 0.047 – this also supports the interpretation stated in our paper that B-blockers were less efficacious than other antihypertensive agents in older patients. We thank Dr. Hoffman for drawing our attention to typographical errors in figures 2A and 2B (see erratum). These were introduced accidentally by us at the editing stage (when we cut and pasted numerical data onto the right hand side of each figure) and were not present in our database when we ran our meta-analyses. As such, the relative risks and confidence intervals reported in our paper are correct and the transcription errors Dr. Hoffman points out do not alter the findings or our interpretation of the findings. Dr. Siebenhofer and colleagues complain that our definition of the composite outcome was unclear in the final published version of our meta- analysis. As any author who has published an article is aware, all journals operate under word limits – while we are grateful to the largesse of the CMAJ editorial team who agreed to publish our meta-analysis even though we were several hundred words over the word limit, we feel it necessary to defend our honour by pointing out that the initial version of our meta-analysis was substantially longer than the final published version and had 4 figures plus 1 table – as a result, the initially submitted version of our manuscript contained far more detail on trial entry criteria, baseline characteristics, and outcome definitions. We regret that in editing down our manuscript we inadvertently caused confusion amongst some readers. Thus, to clarify: our primary analyses were for the composite outcome of cardiovascular deaths (or all-cause deaths where cardiovascular deaths were not reported), MI, or stroke. In light of Dr. Siebenhofer’s concerns about the 12 trials included in figures 2A and 2B of our meta-analysis, it is important to point out that the composite outcomes reported in these 12 trials incorporated cardiovascular mortality in 9 trials, total mortality in 2, and cardiac mortality in 1, and 10 of the 12 trials incorporated fatal and non-fatal MI/stroke in their composite outcomes (with one trial including fatal and non-fatal MI and one trial including only fatal MI/stroke events). As we did not have access to primary study data, we relied upon the endpoint definitions and methods of classification used by the primary trialists (recognizing that this was consistent within trials and thus would be identical across treatment groups within each trial). Dr. Siebenhofer reports a different number of events in the composite outcome for the CAPPP trial than we reported. We believe this discrepancy is due to the fact that while we defined the composite event rates as the proportion of patients experiencing any of the composite events (and counted each participant only once), Dr. Sienbenhofer and colleagues appear to have pooled the number of events for the individual endpoints separately to arrive at their composite event rates. However, this counting of events individually assumes that they are independent and that no patients suffer more than one event - this is clearly not the case and thus we favour the approach we took (an approach also taken by the CAPPP authors in their primary publication). Dr. Siebenhofer also questioned the inclusion of data from CAPPP and STOP 2 (mixed beta blocker studies) in our analysis. While the reasons for including these trials are discussed in the paper, we did report two sensitivity analyses which address Dr. Siebenhofer’s concerns: in one, we excluded the mixed beta blocker trials and in the second we excluded the trials (including CAPPP) not included in the earlier meta-analysis by Lindholm and colleagues. As reported in our publication, these sensitivity analyses yielded results that were not significantly different from the main results. Sincerely, Nadia Khan and Finlay McAlister Erratum: There were typographical errors in the numbers reported on the right hand side of Figures 2A and 2B. None of the typographical errors were incorporated in the analyses and thus none alter the findings or interpretation of the findings. Corrections are summarized below: Figure 2A. For the MRC trial, the denominator for “other drugs” should read 4297 instead of 8654. The overall denominator for the beta blocker group is 14 708 and 14 638 for the “other drugs” group. Figure 2B. The overall denominator for the beta blocker group is 42 598 and 44 582 for the “other drugs” group. The p value for heterogeneity is 0.08 and not 0.8. Conflict of Interest:None declared |
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Andrea Siebenhofer, MD Consultant physician
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andrea.siebenhofer{at}meduni-graz.at Andrea Siebenhofer, MD
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Khan et al. defined the primary outcome for their meta-analyses as the composite of the cardiovascular outcome of death, nonfatal myocardial infarction or nonfatal stroke. First of all, this definition is unclear and leads to the problem that for some studies only cardiovascular deaths and for other studies all cause deaths were included in the analyses. Therefore, we checked the numbers presented from all compared trials in figure 2A and B against the original publications and described the noted discrepancies in further detail in the table.
We recommend recalculating the results and consequently rethinking the interpretation.
Additional authors:
Karl Horvath, MD, Consultant Physician Klaus Jeitler, MD Thomas Gratzer, MD Conflict of Interest:None declared |
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Falk Hoffmann University Bremen, Drug Utilization Research Unit
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hoffmann{at}zes.uni-bremen.de Falk Hoffmann
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Khan and McAlister summarized that ß-blockers are efficacious in younger but not in older patients for hypertension. But their conclusions are based on questionable statistical methods. First, in their methods Khan and McAlister wrote: “Meta-analyses for all outcomes were performed using random-effects models…”. When trying to reproduce their results by entering data into the Review Manager I also observed a significant reduction of cardiovascular events in younger patients (RR 0.86, 95%CI 0.74-0.99). But this result was based on a fixed- effects model. When using the “true” random-effects model, the confidence intervall is wider and includes 1 (RR 0.86, 95%CI 0.75-1.00). Compared to other antihypertensive drugs ß-blockers seemed to raise risk of cardiovascular events in older patients (RR 1.06, 95%CI 1.01-1.10) – but in a fixed-effects model. When using a random-effects model the confidence intervall includes 1 again (RR 1.07, 95%CI 1.00-1.14). Furthermore subjects on ß-blockers and other drugs are not 39010 resp. 40765, but 42598 resp. 44582 (figure 2B, figure 2A includes some calculation errors too). Surprisingly, all other analyses used random-effects model as stated. Using random-effects models as originally described, none of the primary outcomes remain statistically significant. Second, the authors pointed out that there was no evidence of heterogeneity between studies. Pooling trials in figure 2B, they gave a p- value of 0.8. However, the exact result is 0.08. Test for heterogeneity in figure 1B shows a p-value of 0.09. Keeping in mind, that the test has poor power especially when small numbers of studies are included, a cut-off of 0.1 for significance is recommended [1]. Therefore, concluding that there is no heterogeneity seems to be inappropriate. 1 Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003; 327(7414):557-60. Conflict of Interest:None declared |
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Dr. Rajesh Chauhan MH Baroda
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drchauhanrajesh{at}yahoo.com Dr. Rajesh Chauhan
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Dear Editor, There is probably an unusual haste in the diagnosis followed by an equal swiftness in an ‘effective control’ of the recently diagnosed hypertension, following the ‘systematic and time honoured approach’ towards diagnosing and management of hypertension, either as Essential (Primary) Hypertension or as Secondary Hypertension. The largest chunk of recently diagnosed hypertensives, around 90% of all hypertensives, are dumped into the Primary or Essential Hypertension group, and they are accordingly managed lifelong along established parameters and guidelines. Looking dispassionately, it is the patients who are ascribed to the Secondary Hypertension group generally receive optimal care as they receive corrective measures as well as antihypertensive drugs, if necessary. However, not all 90% cases that are categorized as Essential Hypertension are really without a definite cause. During our career as doctors, we have come across many patients whose blood pressures related and corresponded to the (adverse) circumstances. These circumstances can be of brief duration, giving a spike in blood pressure recordings, such as a brief altercation or a show down with the boss. There can be many adverse circumstances or circumstances which are not to one’s likings which may create ‘pressures’ and may influence the readings of blood pressures. As the circumstances do not remain static, so does the blood pressure. Usually the trend we have witnessed is that their condition and the precipitating circumstances are readily perceptible and such patients usually comprise almost 30-40%, or perhaps more, of all hypertensives categorized as Essential or Primary Hypertension. Unable to find work, getting out of job, disharmony at work or at home, unending frustrations, pending crisis, troubling events in rapid succession, financial burdens, always fighting against time, taking care of a handicapped or disabled with chronic illness, terminal illness in the family or of a loved one, etc, are certain examples of circumstances that have the potentials to give rise to “Circumstantial Hypertension” [1,2]. Surely, doctors would have come across such patients in multitudes, as has been our experience. This hypertension shall prevail until such time the ‘circumstances’ remain unchanged. These patients have a tendency of flitting from one consultant to another, for their blood pressures keep fluctuating as is their compliance, forcing frequent change in doses and even in the drugs required for control. Labile Hypertension is the result. Target organs remain undamaged, or the damage is minimal. However, with reversal of ‘circumstances’ and many a times coincident with alternative therapies, magic, prayers, pilgrimage, yoga, meditation, etc, their blood pressures return to normal, but with a propensity to swing back to the raised levels when ‘circumstances’ become unfavorable once again. The maintenance of control of raised blood pressures remains difficult in this group of “Circumstantial Hypertension”. They will need special attention and their associated psychological problems and psychosomatic illnesses will have to be addressed simultaneously. Perhaps if we can distinguish this group separate from the Essential (or Primary) Hypertension, and try managing them differently, better outcomes are possible. Warm regards. Reference: 1. Chauhan R, Singh AK, Chauhan P. ‘Circumstantial’ Hypertension. BMJ 5 Oct 2005. http://bmj.com/cgi/eletters/331/7516/533-a#118439, 5 Oct 2005 2. Chauhan R, Singh AK, Kushwah (Chauhan) P. Consideration for ‘Circumstantial Hypertension’. JABFP 9 December 2005. http://www.jabfp.org/cgi/eletters/17/3/184#80 Conflict of Interest:None declared |
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Bo C Carlberg
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bo.carlberg{at}medicin.umu.se Bo C Carlberg
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Kahn et. al.[1] have re-examined our meta-analysis[2] of beta- blockers in primary hypertension and they came to a different conclusion. Let us clarify why the conclusions differ. Firstly, we examined the effect of beta blocker treatment on the incidence of myocardial infarction, stroke or death separately, whereas Kahn et al. focused on the composite endpoint of them all combined. Antihypertensive drugs, however, do not have the same relative effect on stroke incidence as on myocardial infarction or death. Secondly, we excluded the results of the CAPPP trial[3] since it is impossible to retrieve data on how many patients were on beta-blockers [2]. CAPPP had a PROBE design [3] and had also some other major quality concerns. E.g. randomization was imbalanced with more high risk patients receiving captopril than conventional treatment (diuretics and/or beta blockers). Also, the suboptimum use of captopril once daily was encouraged in an unknown number of patients. There is no possibility to extrapolate the percentage treated with beta blockers in CAPPP from other Scandinavian trials, since both investigators and patients differed between these trials. Finally, treatment of primary hypertension in subjects below 60 years of age is indeed poorly documented regarding cardiovascular outcome. Therefore beta-blockers cannot be recommended to any age-group. References: 1 Khan N, McAlister FA. Re-examining the efficacy of ß-blockers for the treatment of hypertension: a meta-analysis. CMAJ 2006;174:1737-42 2 Lindholm LH, Carlberg B, Samuelsson O. Should beta blockers remain first choice in the treatment of primary hypertension? A meta-analysis. Lancet 2005;366:1545-53 3 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) randomized trial. Lancet 1999;353:611-6 Conflict of Interest:None declared |
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Jubbin. J Jacob Senior Registrar, Department of Endocrinology, Christian Medical College Vellore Tamil Nadu.
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jjacob{at}cmcvellore.ac.in Jubbin. J Jacob
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Beta blockers especially atenelol are among the cheapest anti- hypertensive medications available in developing countries like India primarily because the drug is not protected by patents. The conclusion by Lars Hjalmar Lindholm et al in the Lancet that beta-blockers increased the risk of stroke across the board queered the pitch for the use of beta blockers in our country. In India were substantial information on drugs to doctors are provided by medical representatives of pharma companies, the study published in the Lancet provided a logical argument for the prescription and sale of more expensive anti-hypertensive medications. In this issue of CMAJ Nadia Khan et al provide a more balanced view of beta blocker therapy. By dividing the data into two age groups they have demonstrated efficacy of beta blocker therapy in patients less than 60 years of age in both its anti-hypertensive effects and in reduction of cardiovascular morality without increasing the risk of stroke. A large proportion of patients in India fall in this age group. Use of beta blockers as a first line therapy for hypertension among patients older than 60 years would require a rethink. Low dose diuretic therapy should be the drug of choice in this age group. Thiazide diuretics are equally cheap but are for unexplained reasons (a fear of electrolyte imbalances?) are only rarely prescribed in India as first line drugs for hypertension. Conflict of Interest:None declared |
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AMIN MUHAMMAD GADIT Memorial University of Newfoundland, St. John's, A1B 3V6, Canada
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amin.muhammad{at}med.mun.ca AMIN MUHAMMAD GADIT
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The findings and discussion in the article is informative as well as interesting. With my background exposure of working in Pakistan for many years, it was noticed that beta blockers were commonly prescribed by physicians for treatment of hypertension either as primary or secondary treatment in all ages. In few cases, in order to reduce the heart rate even from 80 beats per minute to lower range for the people with family history of hypertension or cardiac disease as a prophylactic measure was noted. In psychiatric practice also, these therapeutic agents are liberally used for physical manifestations of anxiety and as an adjunct treatment in cases of refractory depression. I wonder if a modified guideline for the use of beta blockers can help the physicians and psychiatrists in the light of this study. Conflict of Interest:None declared |
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