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Rapid Responses: Rapid Responses published:
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Somewhat flawed conclusion.
- D.G. Hackam (10 January 2003)
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Biophysical Semeiotic Constitutions: the most powerful determinants of both complication occurrence
- Sergio Stagnaro (10 January 2003)
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We must be Aware of ‘Surgical Hypertension’ due to Reno-vascular Disease
- Y.C. Chan (11 January 2003)
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ALLHAT shows diuretics fare worst in preserving GFR
- H T Ong (11 January 2003)
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individualise hypertension patients
- dr.manan vasenwala (12 January 2003)
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Thiazides with your pension?
- john s ashcroft (11 February 2003)
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Yet another commentary on the ALLHAT-study
- Martin Wehling, Curt-Engelhorn-Professor of Medicine, Director of the Institute of Clinical Pharmacology (4 April 2003)
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D.G. Hackam, Dept. of Medicine McMaster University, Hamilton, Ontario, Canada
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In an otherwise excellent analysis (1) of the major results of the recently published ALLHAT study (2), Dr. Bryan Williams ends with the following conclusion: "The key message from this trial is that what matters most is getting blood pressure controlled, and that this is overwhelmingly more important than the means."
ALLHAT showed that all blood pressure drugs were not "created" equally (2). Dr. Williams correctly points out important differences in the secondary cause-specific endpoints between chlorthalidone and its active comparators: doxazosin (increased congestive heart failure), lisinopril (increased stroke and coronary endpoints), and amlodipine (increased stroke). For this very reason, the Data Safety Monitoring Board of the ALLHAT trial recommended discontinuance of the doxazosin arm. There are other characteristics of blood pressure drugs other than their effect on so-called "hard endpoints" that are as important as "getting blood pressure controlled." These include cost, adverse effect profile, ease of use (once daily versus multi-daily dosing), and interactions with other drug agents. In all aspects, thiazide-type diuretics come up tops as first-line agents. This was amply shown in the SHEP and MRC studies, where thiazide diuretics were associated with a greater than 40% reduction in the risk of stroke in patients with isolated systolic hypertension; these studies were conducted and completed more than a decade ago. ALLHAT also demonstrated the differences in tolerability between agents, and the particular difficulty in controlling BP to target levels especially with ACE inhibitors in black patients. In choosing a therapeutic agent to lower blood pressure and reduce cardiovascular risk, one must look at not only the blood pressure lowering effect, but also important clinical endpoints we are aiming to prevent, as well as issues such as cost and tolerability. References 1.Williams B. Drug treatment of hypertension. BMJ 2003;326:61-62. 2. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the antihypertensive and lipid lowering treatment to prevent heart attack trial (ALLHAT). JAMA 2002; 288: 2981-2997 Competing interests: None declared |
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Sergio Stagnaro, Specialist in Blood, Gastrointestinal, and Metabolic Diseases. Researcher in Biophysical Semeiotics. Via Erasmo Piaggio 23/8. 16037 Riva Trigoso (Genoa) Italy.
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Sirs, we have to consider accurately the key question that many classes of drugs are available for hypertension treatment, and debate has raged about whether the benefits of treatment are purely a function of the quality of blood pressure control or whether the type of drug used might also be a powerful determinant of outcome (1). In addition, we have to think deeply about the conclusion of a lot of researches, stating that ACE inhibitors and calcium channel blockers were likely to reduce cardiovascular morbidity and mortality by the same order of magnitude as blockers or thiazides, as all physicians’s personal experience allows us to state in a large number of cases, according to ALLHAT Study. In my opinion, however, in all these researches there is unfortunately a fundamental bias: we consider erroneously in hypertension only the "macrovascular" events (e.g., blood pressure values, macrovessel endothelial lesions, macrovascuar compliance), but ignore completely what occur at the level of single patient’s "microvessels as well as microcirculation" (2). In other words, we must reflect finally on the fact that biophysical-semeiotic constitutions are a great reality, although mainly ignored, (See my site, HONCode 233736, http://digilander.libero.it/semeioticabiofisica, and http://digilander.libero.it/microangiologia). Among these numerous constitutions, we can easily recognise in a “quantitative” way, since the first two life decades, beside “Hypertensive Constitution”, also many others, such as “diabetic”, “dyslipidemic”, “arteriosclerotic”, “oncological” (Oncological Terrain) ones, a.s.o. Therefore, we now-a-day are fortunately able to recognise at the bed-side both “hypertensive constitution”, mainly associated to other constitutions, and “pre- hypertensive state”, really a lot of years or decades before hypertension onset (2). Interestingly, to-day we are able to perform clinically both the primary prevention of hypertension, and, in our individual hypertensive patients, the therapeutic monitoring, unavoidable in selecting the best, successful treatment, essential in preventing the well -known hypertensive complications, e.g. CAD (3), thanks to the new physical semeiotics, i.e., Biophysical Semeiotics. 1)Williams B. Drug treatment of hypertension. BMJ 2003;326:61-62 ( 11 January ) 2)Stagnaro-Neri M., Stagnaro S. Stadio pre-ipertensivo e monitoraggio terapeutico della ipertensione arteriosa. Omnia Medica Therapeutica. Archivio, 1-13, 1989-90. 3)Stagnaro-Neri M., Stagnaro S., Deterministic Chaos, Preconditioning and Myocardial Oxygenation evaluated clinically with the aid of Biophysical Semeiotics in the Diagnosis of ischaemic Heart Disease even silent. Acta Med. Medit. 13, 109, 1997. Competing interests: None declared |
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Y.C. Chan, SpR in Surgery, South-East Thames Deanery Department of Surgery, King's College Hospital, Denmark Hill, London SE5 9RS.
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Atherosclerosis is a systemic disease, and whilst most hypertension can be managed medically (1), the presence of concomitant vascular risk factors, end organ damage and established atherosclerotic diseases must be assessed to determine the urgency, intensity and type of treatment (2). All health professionals should be aware that renal artery stenosis (RAS) is an important and readily curable clinical entity that can lead to uncontrolled; and that revascularisation of a stenosed renal artery is associated with preservation of renal function and better control of hypertension, unstable angina, and congestive heart failure. Progression of RAS is relatively common, and carries a great risk of leading to malignant hypertension and may even result in irreversible ischaemic failure of the affected kidney. Recent study has shown that up to one third of elderly patients with heart failure display atherosclerotic RAS (3), and that many patients with peripheral vascular disease have coincident renal artery stenosis (4). Deterioration of renal function and mortality risk are greatest in patients with bilateral RAS. Timely diagnosis of RAS is important as it can carry a more serious prognosis than essential hypertension and is often not amenable to drug treatment. Recent-onset hypertension in a ‘younger’ adult with deranged renal functions and abdominal bruits are characteristics of RAS (5). Recent advances in imaging modalities (such as duplex ultrasound, MAG3 scintigraphy, angiotensin converting enzyme inhibition renography, and magnetic resonance angiography) have allowed easier visibility of the renal vessels. Aggressive risk factor modification and anti-platelet therapy are integral in the management of RAS regardless of the revascularization strategy. Various endovascular and surgical treatments are now available including angioplasty and/or stenting, aorto-renal bypass, renal artery endarterectomy , ex-vivo reconstruction and nephrectomy (6), and these intervention may result in definitive cure of RAS hypertension. References 1. Williams B. Drug treatment of hypertension. BMJ 2003; 326: 61-62 ( 11 January ). 2. Zarnke KB, McAlister FA, Campbell NR, Levine M, Schiffrin EL, Grover S, McKay DW, Myers MG, Wilson TW, Rabkin SW, Feldman RD, Burgess E, Bolli P, Honos G, Lebel M, Mann K, Abbott C, Tobe S, Petrella R, Touyz RM; Canadian Hypertension Recommendations Working Group. The 2001 Canadian recommendations for the management of hypertension: Part one--Assessment for diagnosis, cardiovascular risk, causes and lifestyle modification. Can J Cardiol 2002; 18: 604-624. 3. Zoccali C, Mallamaci F, Finocchiaro P. Atherosclerotic renal artery stenosis: epidemiology, cardiovascular outcomes, and clinical prediction rules. J Am Soc Nephrol 2002; 13 Suppl 3: S179-S183. 4. Pillay WR, Kan YM, Crinnion JN, Wolfe JH; Joint Vascular Research Group, UK. Prospective multicentre study of the natural history of atherosclerotic renal artery stenosis in patients with peripheral vascular disease. Br J Surg 2002; 89: 737-740. 5. Albers FJ. Clinical characteristics of atherosclerotic renovascular disease. Am J Kidney Dis. 1994; 24:636-41. 6. Hines GL. Current thoughts on the management of renovascular disease. Heart Dis 2000; 2: 118-123. Competing interests: None declared |
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H T Ong, Consultant Cardiologist H T Ong Heart Clinic, Penang 10350, MALAYSIA
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Dear Sir, Williams in his editorial suggests that the conclusion can be made from ALLHAT that a diuretic be included in the therapy of hypertensive patients (1). However, the ALLHAT study indicated (table 4) that over a 4 year period, glomerular filtration rate (GFR) was best preserved in the patients on amlodipine and declined most in the diuretic group (2). The ALLHAT authors then dismissed this finding by suggesting that the AASK study had pointed to a detrimental effect of amlodipine on renal function with a faster rate of decline of GFR (3). In fact, a careful review of Figure 3 of the AASK study showed that the effect of amlodipine on GFR depends very much on the status of baseline proteinuria of the patients studied. Thus, patients with a urinary protein to creatinine ratio of >0.22 showed an immediate and more rapid decline of GFR with amlodipine compared to the groups on ramipril or metoprolol. However, this was not the case of the patients with a baseline urinary protein to creatinine ratio <0.22; in fact, after the 3 year follow up, such patients on amlodipine had significantly higher GFR compared to the ramipril and metoprolol groups. Taking the ALLHAT and AASK studies together, it is thus reasonable to initiate patients with hypertensive nephropathy with urinary protein to creatinine ratio <0.22 to amlodipine as this will best preserve GFR. Then when protienuria increases over the threshold urinary protein to creatinine ratio of 0.22, patients can then be changed over to an angiotensin converting enzyme inhibitor (and this better preservation of GFR with the calcium blocker may last 3-4 years). Patients with hypertensive renal inpairment must not be initiated on a diuretic, contrary to the editorial advice of Williams,Alderman and Appel (4,5), given that GFR deteriorates most rapidly in the diuretic treated patients compared to the other agents studied in ALLHAT. References : 1. Williams B. Drug treatment for hypertension : most patients will need a treatment cocktail-including a thiazide diuretic. BMJ 2003; 326: 61-2. 2. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high risk hypertensive patients randomised to angiotensin-coverting enzyme inhibitor or calcium channel blocker vs diuretic: the antihypertensive and lipid lowering treatment to prevent heart attack trial (ALLHAT). JAMA 2002; 288:2981-2997. 3. Wright JT, Bakris G, Greene T, at 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;2421-2431. 4. Alderman MH. Hypertension control and kidney disease : some questions answered, many remain. JAMA 2002; 288:2466-2467. 5. Appel LJ. The verdict from ALLHAT – thiazide diuretics are the preferred initial therapy for hypertension. Competing interests: None declared |
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dr.manan vasenwala, consultant-cardiologist (non-invasive) k.k.heart center, aligarh.202002,INDIA
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the step-up approach for treatment of hypertension is obsolete. also thiazides is not a panacea for all types of hypertension. current view appears that all patients with hypertension should be individualised. the appropriate drug can be selected base on age, sex, black or white, co-morbid conditions like ihd, diabetes, hyperlipidemia, renal impairment , asthma, smoker , obesity etc. also a more futuristic approach is one based on echocardiography. there may be concentric remodelling, concentric hypertrophy, eccentric hypertrophy or mixed. also the ejection fraction, fractional shortening , rwt, left ventricular mass index and diastolic dysfunction may determine which drug would be most appropriate for the patient.no doubt any anti- hypertensives can control blood pressure but may not be suitable for some patients and may lack some features beneficial for associated conditions. thus you have to pick and choose. Competing interests: None declared |
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john s ashcroft, general practitioner old station surgery,heanor rd, ilkeston,derbyshire,DE7 8ES
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As Professor Williams states in his editorial(1), the Allhat study reaffirms the use of thiazide diuretics as a first line treatment for the older population with hypertension; but what about older patients who are not hypertensive? For over twenty years we have seen numerous studies that indicate that thiazide diuretics, in the usual anti-hypertensive doses, preserve bone mineralisation(2), and importantly the use of thiazide diuretics appears to be associated with a 30-40% reduction in the risk of hip fracture(3,4). However,if we are to start our thiazide at the same time we pick-up our pension then we really need a randomised controlled trial. It is perverse that we do not have such a study because thiazides are so cheap. If modern health care is to maximise its potential, then health care agencies need to be prepared to pick up the costs for appropriate research and re-licencing of older drugs, and not just the costs of the patented drugs that phamaceutical companies calculate they can make a profit out of. 1. williams BMJ2003;326:61-62 (11 january) 2. Wasnich RD, et al N Engl J Med 1983 aug 11; 309(6);344-7 3. Cauley JA et al ANN Intern Med 1993 may 1; 118(9);666-73 4. Freskanich D et al Osteoporosis Int 1997;7(1):79-84 Competing interests: None declared |
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Martin Wehling, Curt Engelhorn Institute of Clinical Pharmacology Mannheim, University of Heidelberg, D-68167 Mannheim, Germany, Curt-Engelhorn-Professor of Medicine, Director of the Institute of Clinical Pharmacology
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Even a mega-trial like ALLHAT (1) can miss the reflection of reality. Some related concerns have been raised recently in the Journal (2, 3). I feel the main reason for this is its terrible age which – from the first outline to its completion – is around 12 years. There are several shortcomings which should oblige to exercise caution in the interpretation of the results: 1. A primary treatment arm with ß-blockers is lacking. What is particularly appalling is the fact that despite the prevalence of coronary heart disease and/or diabetes in nearly half the patients, ß-blocker were not given in the first line. This is highly unethical as there is a clear differential indication for ß-blockers in ischemic heart disease and may be even diabetes. How would a modern IRB (ethics committee) decide on this study? 2. Diuretics as first line treatment of hypertension have been accepted for more than two decades. However, their main disadvantage clearly is the high prevalence of non-compliance or the observation of low persistence in clinical reality (4). A clinical trial, even of such tremendous size as the ALLHAT-study, clearly does not re-flect daily life conditions. Promoting a treatment (5) which in reality is not existent at all in many patients is bad advice to the medical community and especially to the patients. 3. In ALLHAT almost half of the patients needed combination treatment. Atenolol, clonidine or reserpine were combination partners. Due to the age of the study latter two compounds appear rather obsolete in the treatment of uncomplicated arterial hypertension. Thus most of the data is as obsolete as the drugs used. 4. The past ten years have taught us valuable lessons about differential therapy of hypertension with modern drugs such as angiotensin-antagonists or have even revitalized ß-blockers because of their life prolonging actions heart failure. No such developments can be reflected by a 12 year old study. 5. The conclusion which might be drawn from ALLHAT that blood pressure has to be lowered by anything which is cheap turns the clock back by at least ten years. Propagation of diuretics leads to non-therapy in a practical setting which is the worst possible treatment. 6. If one lists requirements which have to be met by modern
antihypertensive therapy, ALLHAT should rather be read like this:
7. ALLHAT reflects the inherent problems of all long-term mega-trials: they do not reflect the revolutionary pace of progress in medicine. Therefore, strictly evidence based medicine needs to be combined with thoughtful projections on the base of smaller and more recent trials. ALLHAT is an important study; unfortunately, however, it describes dinosaurs and largely ignores newly developed, versatile and successful mammals. Prof. Dr. Wehling References: (1) The ALLHAT officers and coordinators for the ALLHAT collaborative research group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT) JAMA. 2002; 288(23): 2981-97 (2) Lenzer J. Spin doctors soft pedal data on antihypertensives BMJ. 2003; 326: 170 (3) Williams B. Drug treatment of hypertension BMJ. 2003; 326: 61-62 (4) Caro JJ, Speckman JL, Salas M, Raggio G, Jackson JD. Effect of initial drug choice on persistence with antihypertensive therapy: The importance of actual practice data CMAJ. 1999; 160(1): 41-6 (5) Appel LJ. The verdict from ALLHAT-thiazide diuretics are the preferred initial therapy of hypertension JAMA. 2002; 288(23): 3039-42 Competing interests: None declared |
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