Journal of Human Hypertension (1999) 13, 707–710 1999 Stockton Press. All rights reserved 0950-9240/99 $15.00 http://www.stockton-press.co.uk/jhh ORIGINAL ARTICLE Low dose combinations in the treatment of hypertension: theory and practice NM Kaplan University of Texas, Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75235–8899, USA The recent evolution of drug therapy for hypertension combination with other agents. Such low-dose diuretic has primarily focused on new agents but there has been combinations are rational and their use will almost cer- a renewed interest in the use of low doses of diuretic in tainly increase. Keywords: drug therapy; hypertension; diuretics; low dose combinations Introduction cific coexisting conditions where certain drugs had favourable influences7 (Figure 2). The rationale for Major changes have occurred in the recommen- the first two paths is firmly based on the evidence dations for the initial treatment of hypertension. In from randomised controlled trials (RCTs), while the the US, the recommendations from the 1988 Joint third is more loosely based upon clinical experience National Committee report (JNC-IV) were to use any without the backing of RCTs. of four classes of drugs: diuretics, beta-blockers, The 1999 World Health Organization — Inter- angiotensin-converting enzyme inhibitors (ACEIs), 8 1 national Society of Hypertension guidelines state or calcium antagonists (CAs). In the 1993 JNC-V that: ‘All available drug classes are suitable for the report, only diuretics or beta-blockers were rec- initiation and maintenance of antihypertensive ther- ommended since these were the only drugs that had apy’ but then provide a number of factors that influ- been tested in large-scale randomised controlled ence the choice, leading to a similar list of compel- trials (RCTs) and thereby shown to reduce cardio- 2 ling indications for specific drugs as provided in the vascular morbidity and mortality. JNC-VI report. Despite the appropriate reasoning behind this more restricted recommendation, certainly in keep- ing with the rising demand for ‘evidence-based The advent of low-dose combination medicine’, opposition come from multiple sources therapy that effectively countered the JNC-V position.3 Despite this restricted recommendation, over the Combinations of two or more antihypertensive drugs years from 1990 to 1996, the overall use of diuretics have been available for well over 30 years. However, and beta-blockers fell, while the sales of ACEIs and the rather large doses of the individual components CAs progressively rose4 (Figure 1). often caused adverse effects and an academically The opposition directed against the JNC-V rec- purist attitude favoured the use of individual drugs ommendations came from some academicians5 but whose dose could separately be altered. more forcibly from major market forces,6 extolling In the mid-1990s, an appreciation arose of the the multiple putative advantages of newer agents ability of truly low doses of two drugs to increase while harnessing the natural temptation of prac- overall therapeutic efficacy, while keeping dose- titioners to forego the old in favour of the new, dependent side effects to a minimum. The following thereby keeping on the cutting edge of medical prac- three drugs are now approved for initial therapy in tice. Europe or the US: one with low dose of the ACEI Meanwhile, multiple controlled clinical trials perindopril (2 mg) and very low dose of the non- with the newer agents began to appear that docu- thiazide diuretic indapamide (0.625 mg);9 two mented their special attributes in a variety of spe- others with low dose of an ACEI (benazepril) or cific situations. As a result, the 1997 sixth JNC report a low dose of a beta-blocker, bisoprolol, both with (JNC-VI) offered three pathways for initial therapy: low doses of the diuretic hydrochlorothiazide (1) for uncomplicated hypertension; (2) for four (6.25 mg).10,11 As stated in the JNC-VI: ‘Newly ‘compelling’ indications; and (3) for a variety of spe- developed formulations provide additional medi- cation choices. For example, combinations of low doses of two agents from different classes have been Corrospondence: Dr Norman M Kaplan shown to provide additional antihypertensive effi- Received 1 November 1998; revised 29 April 1999; accepted 25 cacy, thereby minimising the likelihood of dose- May 1999 dependent adverse effects’.7 As seen in Figure 2, Low dose combinations in the treatment of hypertension NM Kaplan 708 Figure 1 Sales, in millions, of antihypertensive drugs in the US from 1986 to 1997. (From Kaplan: Clinical Hypertension 7th edn, 1998, p 189). JNC-VI indicates the appropriateness of low dose low-dose diuretic along with low-doses of all the combinations for initial therapy. other classes of antihypertensive drugs. The 1999 WHO-ISH guidelines provide a similar The non-thiazide diuretic indapamide fulfills the affirmation of the value of combination therapy: overall criteria for a diuretic to be used in combi- ‘Effective drug combinations utilize drugs from nation with other antihypertensive agents since it different classes in order to obtain the additive effectively lowers the blood pressure and does not hypotensive effect that comes from combining drugs compromise serum cholesterol14 or plasma glucose with different primary actions, while minimising levels15 while it also reduces left ventricular the compensations that limit the fall in blood press- hypertrophy (LVH).16 The formulation of perindop- ure’.8 These guidelines also recommend low dose ril and idapamide has been shown to provide mul- combinations to initiate therapy, stating that ‘the use tiple ancillary benefits in an experimental model of of the fixed low-dose combinations that are increas- salt-sensitive hypertension.17 ingly available in the United States and Europe may Hopefully, the use of such low-dose combinations be advantageous’. will provide effective reductions of blood pressure with minimal adverse effects, thereby improving The importance of a diuretic component patient adherence to long-term therapy and provid- ing additional protection against premature cardio- A rapidly expanding group of low-dose combination vascular disease. formulations are being marketed. Although some of the combinations that do not include a diuretic may be appropriate for second-line therapy,12 only com- binations with a low dose of diuretic are currently Other combinations approved in the US for initial therapy. This position will most likely hold. Both the 1997 JNC-VI and the 1999 WHO-ISH guide- Again, JNC-VI provides the rationale, stating that: lines provide a number of other rational combi- ‘If a diuretic is not chosen as the first drug, it usually nations of drugs from different classes that do not indicated as a second-step agent because its addition include a low-dose diuretic. Although such combi- will enhance the effects of other agents’.7 This nations may provide good blood pressure control ability of sub-maximal doses of diuretic to enhance and ancillary benefits, they seem less suitable for efficacy has been demonstrated with all other classes initial therapy than those that include a low dose of of drugs.4 Moreover, the tendency for increased diuretic. However, the increasing recognition that at retention of sodium by the hypertensive kidney as least two drugs and often three or more are needed non-diuretic drugs cause the blood pressure to fall to achieve the degree of antihypertensive effect that has long been recognised as a cause of loss of antihy- is needed to protect high risk patients such as hyper- pertensive efficacy that can immediately be restored tensive diabetics,18,19 will provide additional by addition of a diuretic.13 Therefore, there will momentum to the use of various combination ther- likely be a continued growth of combinations of apies. Low dose combinations in the treatment of hypertension NM Kaplan 709 Figure 2 Algorithm for the treatment of hypertension, ACE indicates angiotensin-converting enzyme; ISA, intrinsic sympathomimetic activity. (From Arch Intern Med 1997; 157: 2430). References on Prevention. Detection, Evaluation and Treatment of High Blood Pressure. Arch Intern Med 1997; 157: 1 Joint National Committee on Detection, Evaluation and 2413–2444. Treatment of High Blood Pressure. The 1988 Report of 8 Guidelines Subcomittee. 1999 World Health Organiza- the Joint National Committee on Detection, Evaluation tion-International Society of Hypertension Guidelines and Treatment of High Blood Pressure. Arch Intern for the management of hypertension. J Hypertens 1999; Med 1988; 48: 1023–1038. 17: 151–183. 2 Joint National Committee on the Detection, Evaluation, 9 Meyrier A et al. Fixed low-dose perindopril-indapam- and Treatment of High Blood Pressure. The Fifth ide combination with hypertensive patients with Report of the Joint National Committee on Detection, chronic renal failure. Am J Hypertens 1998; 11: Evaluation, and Treatment of High Blood Pressure 1087–1092. (JNC V). Arch Intern Med 1993; 153: 154–183. 10 Chrysant SG et al. Effects of benazepril and hydrochlo- 3 Barreuther A. Academic detailing to influence rothiazide given alone and in low and high dose com- prescribing. J Managed Care Pharm 1997; 3: 631–638. binations on blood pressure in patients with hyperten- 4 Kaplan NM. Treatment of Hypertension: Drug Ther- sion. Arch Fam Med 1996; 5: 17–24. apy. In: Clinical Hypertension, 7th edn. Williams and 11 Frishman WH et al. A multifactorial trial design to Wilkins: Baltimore, 1998. assess combination therapy in hypertension: treatment 5 Weber MA, Laragh JH. Hypertension: steps forward and with bisoprolol and hydrochlorothiazide. Arch Intern steps backward. Arch Intern Med 1993; 153: 149–152. Med 1994; 154: 1461–1468. 6 Siegel D, Lopez J. Trends in antihypertensive drug use 12 Gradman AH et al for the Enalapril-Felodipine ER fac- in the United States: do the JNC V recommendations torial study group. Combined enalapril and felodipine affect prescribing. JAMA 1997; 278: 1745–1748. extended release (ER) for systemic hypertension.