Highlights of a satellite symposium held during the XXIII Congress of the European Society of Cardiology Low-dose combination therapy in hypertension.
Is it time for a change in treatment recommendations? A satellite symposium entitled Low-dosecombination therapy in hypertension. Is ittime for a change in treatment recommenda-tions? was held during the XXIII Congress ofthe European Society of Cardiology in Stock-holm, Sweden, September 1-5, 2001, topresent newer data on the management ofhypertension and discuss clinical findings on Lars H Lindholm
the beneficial effects of a low-dose combina-tion therapy. This report summarizes the main First-line treatment of hypertension with
results from the symposium. The Meeting was a drug containing two medications
chaired by Marvin Moser (US) and Lars H
(bisoprolol, a beta1-selective beta-blocker,
Lindholm (Sweden) and was organized by
and hydrochlorothiazide) in subtherapeutic
dosages may represent a new treatment
concept in hypertension.
Clinical data with such a low-dose combina-
tion have proven excellent efficacy, at least
comparable to amlodipine and superior to
enalapril, with placebo-like side effects.
The fixed low-dose combination simplifies the dosing regimen, improves compliance,and reduces drop-out rates, leading to lower strongly that even treating people over the age of 80, with no symptoms, is beneficial.
You reduce stroke and heart failure - you may not prolong their lives, but you reduce these drugs in higher doses. The use of a heart failure, the data from a large number and diuretic results in a significant blood reduces the occurence of heart failure, by pressure reduction with a side-effect profile should not forget is that treating slightly ele-vated BP will prevent the occurrence ofheart failure in the first place.' ventricular hypertrophy (LVH), which is a major independent risk for sudden death,arrhythmias and heart failure, according to Dr Moser. He said that regression of exist- ing LVH may be achieved with a variety of selecting drugs and drug combinations that aid patient compliance, according to Dr
Lars H Lindholm (Department of Public
Health and Clinical Medicine, Umeå Uni- versity, Umeå, Sweden). Pointing out that from the pooled data from 6 controlled trials blood pressure (BP) control offers proven risk reductions of about 40% for stroke and progression to severe hypertension (>200- said: 'I think we can agree that, when treat- ing hypertension, few patients today attain in the active treatment group [1]. Dr Moser the treatment goals and I think that it is compliance that is the crux - what we have patients will or will not progress to severe to do is to find the right drug for each of our disease, but you can be reassured that if you treat hypertension you will prevent pro- hypertension therapy reflects the 'Rule ofHalves': 'Only half of hypertensives havebeen found, only half of those who have been found have been treated, and onlyhalf of those have been properly treated, ending up with [a control rate] of 12-14%.'In particular, he called for better control of systolic BP (SBP), as well as diastolic BP National Committee (JNC) [2] and the World Health Organization-International Society hypertension was echoed by Dr Marvin
Moser (Clinical Professor of Medicine, Yale
pointed out that these were based on trials School of Medicine, USA) who said that drugs. For this and other reasons, the 6th added: 'Regardless of how we treat [hyper- tensives], we must begin to pay more atten- by suggesting that the low dose combina- tion to the SBP. Recent data suggest very tions are appropriate for initial therapy. microvascular complications than relatively tight glucose control.‘ He suggested that lowered for people with diabetes and renal recent trial findings (see Figure 1).
modify the WHO-ISH conclusion that lowering BP per se with any effective agentis beneficial, since there is now evidence from a variety of studies that calcium channelblockers (CCBs) are about 20-25% less effective than ACE inhibitors and other anti- or even lower in subjects with diabetes or renal disease hypertensive drugs in reducing risks ofmyocardial infarction and chronic heart Initial Drug Therapy*: Uncomplicated Hypertension** Low-dose combinations may be appropriate suitable for initial therapy, should now be * Unless contraindicated ** Based on randomized clinical trial removed as first step therapy, due to find-ings of higher cardiovascular event rates Figure1: Suggested guidelines for the initial pharmaco- with doxazosin compared to a diuretic [5].
logic treatment of hypertension (JNC VI).
initial antihypertensive treatment regimens shown that, contrary to earlier opinion, they can be as successfully treated with beta- gression of renal disease [6, 7, 8].
he said: ’Diuretics/beta-blockers have held parisons with other agents and they should control is extremely important (see Figure 2).
majority of our patients are going to end up studies available, looking at tight BP control very good sense - especially in high-risk versus tight glucose control, you find tight patients, such as the diabetic patient with BP control achieved a greater reduction in hyperlipidemia, the smoker, the older per- son - to start these people on combinationtherapy.‘ basis on several recent studies, was thatACE inhibitors should be recommended as potential of diuretics for adverse metabolic effects as ’a myth‘, Dr Moser said: ’There have been many . studies . that put to rest the myth that these drugs over the long term have adverse effects on lipids or blood glu- cose levels. In fact, in several studies, suchas the diuretic based SHEP trial, people Figure 2: Comparative effects on risk of tight glucose with the highest cholesterols had just as control versus tight BP control. (DM = diabetes mellitus) good results as people with the lowest.‘ • Simplicity of regimen• Simple titration process• Improved compliance• Cost advantage• Potentiation of efficacy• Reduction in side effects• Offsetting of undesirable side effects L Michael Prisant
fixed low-dose combination of the highlyselective beta-blocker bisoprolol and the In its 6th report the JNC recommended the diuretic hydrochlorothiazide (HCTZ) for the use of low dose combinations of drugs for first-line treatment of hypertension [2].
tension. First, a multifactorial trial [10] was Picking up on this lead, Dr L Michael
carried out, with combinations of bisoprolol Prisant (Professor of Medicine, Hyperten-
sion Unit, Section of Cardiology, Medical College of Georgia, Augusta, Georgia, from this study suggested that the lowest USA) advocated the use of low doses of a diuretic and a beta-blocker in combination.
He said that they are effective in controlling BP in most patients, have placebo-like side with Bisoprolol 10 mg and the most effec- effects, and should be considered as first- tive combination with minimal hypokalemia drug titration has the disadvantage that as [11] in which patients were randomized to events. The alternative of drug substitution, placebo, bisoprolol 5 mg, bisoprolol 5 mg/ advantage that the patient often loses con- fidence in the physician as drug after drug is tried, whilst in practice most patients control. He therefore advocated first-line use of fixed low-dose combinations, which have many potential benefits (see display), such benefits, with the fixed low-dose combi- nation was rare, reaching a rate of 0.7%, effects are related to the levels of the indi- was tested against two drugs commonlyprescribed for hypertension, namely, theACE inhibitor enalapril (5 -20 mg daily) andthe CCB amlodipine (2.5 -10 mg daily) [12].
After a 4-week washout period, the drugswere titrated over a 4-week period to cantly greater than the 45% response rate with enalapril (p< 0.01). Reductions in DBP amlodipine, and enalapril were, respective- Significantly, Dr Prisant reported that the rate of adverse events was lower with randomized trials showed no difference in the low-dose bisoprolol/HCTZ combination the frequency of erectile dysfunction with (29%; p = 0.04), than with the CCB (42%) therapies (see Figure 4) [14].
rate with low-dose bisoprolol/HCTZ wassimilar to amlodipine, but both were superiorto enalapril. A further trial was performed.‘ In this study [13], the dose ranges were thesame, with the exception that higher doses of enalapril were allowed (5 mg daily to 20 mg twice daily) and a placebo group was line achieved in this study for the low-dose Rate of Self-Reported Erectile Dysfunction (%) 11.8 / 9.9, 9.8 / 9.0, and 1.1 / 1.9 mmHg and There was no increase in the rate of sexual dysfunction among group relative to placebo. (50) control rates of 84% (bisoprolol / HCTZ),70% (amlodipine), 52% (enalapril) and Figure 4: Self-reported erectile dysfunction in prospec- tive randomized trials, showing no difference among said that statistical analysis of the findings showed that ’the low-dose bisoprolol / HCTZcombination was superior to enalapril andplacebo for SBP, and for DBP it was Commenting on these studies with the low-dose bisoprolol / HCTZ 6.25 mg combi- nation, Dr Prisant said: ’It’s a very effectiveapproach to trying to lower BP. I’m surecontrol will be better, so we should considerlow-dose combination therapy to provide additional efficacy, with fewer adverse Figure 3: Intent-to-treat patients: control rates Athanase Benetos
relationship between the reduction of SBPand the improvement in QOL scores, which In the elderly, isolated systolic hypertension means that the reduction of SBP is not only can be as effectively treated with the fixed something that reduces long-term risk, but also if it’s progressive and correctly made it with the CCB amlodipine, reported Dr
Athanase Benetos (Senior Consultant in
Hypertension, Broussais Hospital, Paris, F ). Reductions in BP after 12 weeks’ treat- tension, he explained that with the progres- ment were similar for the combination and sive stiffening of the arteries found in older and 19.6/2.4 mmHg) (see Figure 5), the the prognostic significance of DBP, SBP,and pulse pressure (PP = SBP - DBP).
Presenting data from the FraminghamStudy he showed that until about the age of 55-60 years there are parallel increases in SBP and DBP, but thereafter DBP decreases and so the guidelines to reduce BP as muchas possible are valid. But in older patients there is a disruption in the relationshipbetween SBP and DBP. Isolated systolic hypertensive subjects over 60 years ofage.‘ Figure 5: Changes of systolic and diastolic BP during treatment in isolated systolic hypertensives. Reproduced with permission from the Am Heart J Publishing Group.
Am Heart J 2000; 140: e 14.
showed that, for a given level of SBP, thereis a U-shaped relationship between cardio-vascular risk and DBP. He said: ’There was frequencies of adverse events were similar a high mortality in those with low DBP and (39% and 40%) (see Figure 6), and both also those with very high DBP. The lowest cardiovascular [event] rates occurred at a ty of life (QOL) scores (2.5 and 3.2) [15].
Dr Benetos commented: ’It’s important to say that in this study there was a close that, for a given SBP, a lower DBP was asso- ciated with a higher CHD risk, the effectbeing more marked at higher values of SBP.
Interpreting these trends for the practi- tioner, Dr Benetos proposed a novelapproach to assessing the risks of hyper-tension in people of various ages: ’Whenwe deal with young people (men < 50 years, women < 60 years), both SBP and with older people (men 50 -70 years,women 60 - 80 years), SBP is more impor- (men > 70 years, women > 80 years), PPmay be the most useful determinant of risk, reflects a very poor arterial system. It’s not a question of asking if it’s good to have alow or a high DBP, but [considering] how with isolated systolic hypertension are atleast as great as those with diastolic and systolic hypertension, whilst in older people they are greater. He added: ’By ”older“ I mean an older arterial system. With obesepatients, those with diabetes, and high-risk is effective in controlling blood pres-sure, have placebo-like side effects,and should be considered as first-line therapy for hypertension References
[1] Moser M, Herbert P. Prevention of disease progres- [9] Oster JR, Epstein M. Fixed-dose combination med- sion, left ventricular hypertrophy and congestive heart ications for the treatment of hypertension: a critical failure in the hypertension treatment trials. J Am Coll review. J Clin Hypertens 1987; 3: 278-93.
[10] Frishman WH, Bryzinski BS, Coulson LR, DeQuattro [2] Joint National Committee. The sixth report of the joint VL, Vlachakis ND, Mroczek WJ, et al. A multifactorial trial national committee on prevention, detection, evaluation design to assess combination therapy in hypertension.
and treatment of high blood pressure (JNC VI). Arch Treatment with bisoprolol and hydrochlorothiazide. Arch Intern Med 1997; 157: 2413-46. Correction, ibid. 1998; [11] Frishman WH, Burris JF, Mroczek WJ, Weir MR, Ale- [3] World Health Organization-International Society of mayehu D, Simon JS, et al. First-line therapy option with Hypertension. World Health Organization-International low-dose bisoprolol fumarate and low-dose Society of Hypertension Guidelines for the Management hydrochlorothiazide in patients with stage I and stage II of Hypertension. J Hypertens 1999; 17: 151-83.
systemic hypertension. J Clin Pharmacol 1995; 35: 182-8.
[4] United Kingdom Prospective Diabetes Study Group.
[12] Prisant LM, Weir MR, Papademetriou V, Weber MA, Tight blood pressure control and risk of macrovascular Adegbile IA, Alemayehu D, et al. Low-dose drug combi- and microvascular complications in type 2 diabetes: nation therapy: an alternative first-line approach to hypertension treatment. Am Heart J 1995; 130: 359-66.
[5] Antihypertensive Therapy and Lipid Lowering Heart [13] Neutel JM, Rolf CN, Valentine SN, Li J, Lucas C, Attack Trial (ALLHAT) Collaborative Research Group.
Marmorstein BL. Low-dose combination therapy as first- Major cardiovascular events in hypertensive patients line treatment of mild-to-moderate hypertension: the effi- randomized to doxazosin vs chlorthalidone: the Antihy- cacy and safety of bisoprolol/HCTZ versus amlodipine, pertensive and Lipid-Lowering Treatment to Prevent enalapril, and placebo. Cardiovasc Rev Rep 1996; 17: Heart Attack Trial (ALLHAT). JAMA 2000; 283: 1967-75.
[6] Reduction of Endpoints in NIDDM with the [14] Prisant LM, Weir MR, Frishman WH, Neutel JM, Angiotensin II Antagonist Losartan Study (RENAAL).
Davidov ME, Lewin AJ. Self reported sexual dysfunction Effects of Losartan on renal and cardiovascular out- in men and women treated with bisoprolol, hydro- comes in patients with type 2 diabetes and nephropathy.
chlorothiazide, enalapril, amlodipine, placebo or bisopro- lol/hydrochlorothiazide. J Clin Hypertens 1999; 1: 22-6.
[7] Irbesartan in Patients with Type 2 Diabetes and [15] Benetos A, Consoli S, Safavian A, Dubanchet A, Microalbuminuria (IRMA) Study Group. The effect of irbe- Safar M. Efficacy, safety, and effects on quality of life of sartan on the development of diabetic nephropathy in bisoprolol/hydrochlorothiazide versus amlodipine in patients with type 2 diabetes. N Engl J Med 2001; elderly patients with systolic hypertension. Am Heart J [8] Irbesartan Diabetic Nephropathy Trial (IDNT) Colla-borative Study Group. Renoprotective effect of theangiotensin-receptor antagonist irbesartan in patientswith nephropathy due to type 2 diabetes. N Engl J Med2001; 345: 851.
Sponsored by Merck KGaA, D-64271 Darmstadt, Germany This is a sponsored publication. The views expressed in this publication are those of the contributing authors and are not be construed as the opinions or recommendations of the sponsor Merck KGaA.


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