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Chronotherapeutics of ramipril and the HOPE study
- Martin S Knapp (14 October 2003)
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Bd dose for ramipril
- kausar Jafri (9 November 2009)
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Martin S Knapp, nephrologist Mildura Nephrology, 186, Thirteenth St., Mildra, Victoria, 3500, Australia
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Taylor (Sept 20) raises several points of interest in his comments on the HOPE study, with the possibility that the time of administration of ramipril in that study may have confounded interpretation. Taylor draws attention to an aspect of the Hope study protocol which has previously received little attention, ie that the protocol requested ramipril be taken at nighttime. He also points out that in a sub-study the data from 24 hour studies of blood pressure after ramipril reported a peak effect 3 to 6 hours after administration, which "waned" by 12 hours after administration…the time of blood pressure measurement in those taking a nocturnal dose. The possible importance of these questions was partly discussed in the author's reply, but only in the context of any possible influence on the HOPE study conclusions ie that ramipril has an effect on cardiovascular outcomes that is larger than could be anticipated by the recorded falls in blood pressure, but blood pressures were taken - if following the protocol - in the daytime 12- 18 hours after (nocturnal) administration, and not at the time of peak effect. Taylor asked that the authors "come clean" on "just how many of their subjects followed the original protocol and took ramipril at night".Bosch and Yusuf do not address that question in their reply (Sept 20). Taylor’s comments reinforce questions that should be asked by clinicians when prescribing ramipril, or any other medication and by those designing protocols for clinical trials. At what time of day should the medication be taken? Which medications for which conditions might be more effective taken in divided doses? With the currently fashionable "once daily" administration it is unusual to locate data on what time of day to propose a medication is taken. This question in relation to ramipril and other pharmaceuticals that slow the progress of kidney failure is of particular importance to those of us treating progressive kidney failure. Current guidelines are based on studies that do not usually provide any comment on the time of day that medication was prescribed, or with information on whether this advice was followed. It is becoming increasingly obvious that some patients with progressive kidney failure are "responders" and stabalise, or even improve, kidney function, with medication and blood pressure reductions at or below current guidelines. Others with progressive kidney failure do not respond and kidney failure progreses to dialysis or death To reach the “target” lower blood pressure and achieve reducing albuminuria or proteinuria and stabilized or improved kidney function I have often moved ramipril, and other medications, to nocturnal or divided (night and morning) doses. A majority of patients in my practice are now stablised or improving (1); but there is uncertainty whether this is because I plan therapy to get better nocturnal blood pressure control when a patient does not stop deteriorating. In 1963 Davies, Shaw and I (2) suggested, after 24 hour studies of blood pressure contrasting patients with "essential" hypertension with “malignant” hypertension, that deterioration in kidney function might be a feature of those patients whose blood pressure did not fall (or not fall enough) when asleep. Recently several groups have demonstrated that those in type 2 diabetics with abnormal sleeping/ nocturnal blood pressure proceed to microalbuminuria (3). In 1978, in an unattributed editorial in your journal (4), which I provided following the first international conference on chronotherepeutics, I have urged clinicians and clinical trialists to be more thoughtful about the time of administration of medications in relation to biological cycles, including the circadian cycle,or, at least, to record the clock time of administration…or better the time of administration in relation to the sleep/wake cycle (5). The continued debates over the therapeutic efficacy and side-effect profile of many medications, including ramipril and others with similar pharmacology, aspirin, hormone replacement therapy and growth factors, depend upon studies that make no reference to the time of administration, even when only one dose each day is administered. It is not satisfactory that those who have taken responsibility for protocol design in the current era are ignoring this potentially critical variable, as do those who conduct meta-analyses and the majority of those who contribute review articles and editorials. It is important that Professor Bosch and Dr Yosuf "come clean" as requested by Professor Taylor. Investigators in this, and other areas of pharmacological research, should give further consideration to the possible importance of the chronology of therapeutics. Martin Knapp, Nephrologist. 1 Knapp MS. A transverse and longitudinal audit of pre-dialysis renal failure in a non-metropolitan clinic. Nephrology 2003: 8 (supplement) A90 (abstract) 2 Shaw, DB., Knapp,M., Davies DH. Changes in the blood pressure of hypertensives during sleep. Lancet, 1963: 797-798 3 Lurbe E, Redon J, Kesani A, Pascual JM, Tacons J, Alvarez V, Batlle D. Increase in nocturnal blood pressure and progression to microalbuminuria in type 1 diabetes. N Engl J Med. 2002 Sep 12;347(11):797-805. 4 Knapp, MS (unattributed). Chronotherapeutics; a new clinical science (editorial). Brit.Med.J 1978 i. 1376 5 Knapp MS. Chronotherapeutics: Theory and Practice. Current Therapeutics 1991. 97-105 Competing interests: None declared |
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kausar Jafri, locum gp st4 8hl
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I was under the impression that Ramipril was more beneficial in hypertension because of BD dose- to reduce the burden of blood pressure- so why is it currently promoted as once a day medication Competing interests: None declared |
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