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Drug Therapy: Fixed Combinations in
Antihypertensive Treatment

Alberto Villamil, MD

Hypertension Department, ICBA and Dr. Cosme Argerich Hospital,
Buenos Aires, Argentina

   Hypertension is one of the most important pathologies in everyday practice due to its high prevalence and its status as a risk factor for stroke, coronary artery disease, heart failure and end stage renal disease (ESRD). Although the available trials clearly show the benefits of blood pressure (BP) reduction, they do not define with precision the desired reduction in BP for a number of situations. In fact, due to the continuous relation between BP and risk, the goal of reducing BP to the greater extent possible seems appropriate, since different epidemiological studies (1-3) demonstrated that, even at "normal" levels, a lower BP is associated with lower risk of stroke, renal function impairment or heart failure.

   Thus, the Joint National Committee (JNC) in its Sixth Communication as well as the World Health Organization (WHO) and the International Hypertension Society (ISH) consider that a patient is "controlled" when BP is steadily below 140/190 mmHg (systolic/diastolic blood pressure, respectively [SBP/DBP]). However, many doubts arise when trying to define "control" for patients with other associated risk factors, target organ damage or previous cardiovascular disease. In this context, a normal (< 130/85 mmHg) or optimal (120/80 mmHg) BP appears to be a desirable goal in young patients, middle-aged adults and in diabetics or patients with renal disease (particularly when they present with proteinuria), and at least a high-normal BP in the elderly (< 140/90 mmHg).

   Traditionally, monotherapy is recommended when initiating antihypertensive treatment except in patients in phase 3 (severe), for which a therapy with two drugs is recommended (1). Lately (2), stepped care approaches for the use of specific drugs have been abandoned; nowadays, physicians can select any of the following therapeutic options: diuretics, ß-blockers a-blockers, calcium-channel blockers, ACE inhibitor or angiotensin-II receptor antagonists, according to the specific needs of the patients.

   However, hypertension is a highly heterogeneous disease, and depends on the interplay of many pathophysiological factors ranging from genetics to environment; it is not surprising, then, that each patient responds differently to distinct antihypertensive drugs.

   When a satisfactory control (sustained BP < 140/90 mmHg) is not achieved with monotherapy, one of the following alternatives is recommended: maximum dose titration, drug change or addition of a second, complementary drug. This therapeutic plan would seem the logical choice to make, but bears important limitations:

   In everyday practice, normotension is only poorly attained with these recommendations. For example, only 27% of hypertensives are controlled in the USA, less than 6% in the UK, 16% in Canada and less than 13% in Argentina. (1,8) In all these cases, monotherapy is prescribed in 60% or more(9) of treated hypertensives. These insufficient outcomes are quite predictable since, as the WHO and the ISH indicate in their report (2): "When drugs form the main classes available are used as monotherapy at the recommended doses, they produce very similar blood pressure reductions. In general, the sizes of the blood pressure reductions increase with the initial level of blood pressure, but typically, the placebo adjusted reductions average about 4-8% for both systolic and diastolic blood pressure. Thus for patients with blood pressure of about 160/95 mmHg, the usual reduction produced by monotherapy would be about 7-13 mmHg systolic and 4-8 mmHg diastolic. Clearly, for many patients with hypertension, such reductions in blood pressure would not restore optimal or even nonhypertensive blood pressure levels."

   Physicians seldom modify the therapeutic regimen in uncontrolled patients on monotherapy, and many are reluctant to add a second or third drug when BP goals are not achieved. Trials in different countries have shown that physicians, in everyday practice, modify the treatment only in 1 of every 4-5 uncontrolled hypertensive patients, although they indicate more frequent control visits. 10,11

   A single drug acts mainly on a single pathophysiological mechanism, whereas it is widely known that hypertension is a multifactorial pathology, in which many mechanisms interact. It is also known that when a particular system is blocked, others systems are activated that reduce the initial therapeutic effect. For example, sodium retention induced by ß-blockers or vasodilators as minoxidyl causes pseudotolerance, with loss of antihypertensive effect and calls for the prescription of a diuretic in order to neutralize this mechanism. (12,13)

   Monotherapy requires drugs with an adequate dose-effect curve, because if a satisfactory response is not achieved with the initial dose, it must be increased. In addition, selected drugs should have a prolonged half-life (achieving optimal trough-peak index) to guarantee adequate therapeutic action over a 24 h period.

   Some patients respond to any drug, others only to a single drug and it is not possible to predict the response in a particular patient. A study in the UK (14) demonstrated that in everyday practice, independently of the type of drug initially selected, the physician indicates a change in monotherapy in more than 50% percent of patients during the initial six months of therapy, without a successful control of BP. Thus, although a sequential approach for each patient may have good results, at the same time is troublesome and requires more visits over a number of months.

   Even in studies in which initial monotherapy could be highly up-titrated, researchers added a second drug in 50-70% of cases, proving that seldom can normotension be obtained with monotherapy. (15-19)
This situation requires alternative answers. First, to continue the search for new and more effective antihypertensive drugs than those presently used. Despite that nowadays important pharmaceutical research is being done, this process will take time and it cannot be assured whether they will succeed or not. The problem calls for a rapid implementation of alternative solutions.

   If initial monotherapy fails to achieve normotension in a high number of patients, the option of therapy with two drugs at low doses seems adequate.

   From a pharmacological standpoint, the association of drugs is optimal when they act through different mechanisms and are complementary. The use of this type of association is widely extended over a number of fields as oncology (chemotherapeutic combinations), infectious diseases (tuberculosis, AIDS, mixed infections, etc.), osteopathy (treatment of osteoporosis) and in cardiology (treatment of heart failure with different drugs). In all cases, the use of more than one drug is accepted and fixed combinations are frequently used. On the contrary, despite that since 1960 fixed combinations with two antihypertensive drugs are available (Table 1), in this field the physician is still reluctant to use them; they are actually mere therapeutic instruments that naturally have its pros and cons.

Some of the advantages are:
· The overwhelming evidence about the higher therapeutic response to a combination of two antihypertensive drugs. In fact, recently issued international l recommendations indicate that: "Combination therapy of several of the available drug classes has been shown to produce blood pressure reductions that are greater than those produced by any group of individual agents used alone. The HOT study, (20) in which blood pressure was lowered to below 90 mmHg in over 90% of patients, demonstrated that combination therapy was necessary in 70% of participants. Combinations with fully additive hypotensive effects will deliver blood pressure reductions that are around twice as great as those obtained with a single drug, of the order of 8-15%, or 12-22 mmHg systolic and 7-14 mmHg diastolic for patients with blood pressure of 160/95 mmHg"

   For example, in the HOT study (20) diastolic normotension (<90 mmHg) was attained in almost 90% of patients, but the combination of at least two drugs was necessary in 70% of participants. In Argentina, in a recent evaluation of the outcomes in a private clinic and a public hospital, diastolic normotension was achieved in 82% of all cases. Again, 69% of patients required at least two drugs. (21)

· One of the major reasons for the combination of drugs is that, while reaching a superior clinical effectiveness, lower doses of both associated drugs can be used, and this results in a lower incidence of adverse effects and therefore, in better patient-adherence to treatment. (Table 2)

   For example, diuretics stimulate the angiotensin-renin system and allow through this mechanism an enhanced activity of ACE inhibitors as well as angiotensin receptor antagonists. Beta-blockers can also neutralize the reflex tachycardia that a number of vasodilators or dyhidropiridinic calcium-channel blockers may induce. Effective combinations result from the association of different types of drugs that produce an additive BP lowering effect, minimizing compensatory mechanisms that limit the reduction of BP. (13,15) (Table 3)

· Fixed combinations are less expensive than separate prescription of drugs. This is a key component in the treatment of chronic diseases like hypertension, which require medication over long periods or even for a lifetime.

· Overall, fixed combinations make management easier for the physician when compared to free association of drugs. Also, it is well-known that the therapeutic regimen may influence patient-compliance, clearly indicating the superiority of single tablet administration in once-daily regimens. (22)

· Target-organ damage associated with hypertension may be effectively prevented or reverted with combination therapy. Metaanalyses (13) have shown that combination therapy regresses left-ventricular hypertrophy in a much greater extent than monotherapy.

   In addition, in diabetics, the progression to ESRD is reduced with antihypertensive treatment. In FACET study (23), those hypertensive diabetics treated with lisinopril progressed to less ESRD than those treated with amlodipine, but the best result was obtained with a combination of both drugs, suggesting that a higher antihypertensive effect is associated with nephroprotection.

Among the possible disadvantages of fixed combinations are:
· Desired combinations or a variety of doses are not always available, although new ones are being offered continuously.

· Concern about the consequences of overtreatment. The potential risk of reducing DBP below 85 mmHg ("J" curve hypothesis) and a resultant higher risk of coronary events have not been confirmed, and were not observed in a number of studies. (24-26) In fact, the HOT study (20) evaluated the results in hypertensives randomized to different DBP goals (< 90, < 85 or < 80 mmHg) and confirmed the absence of increased risk in the group with a goal of DBP <80 mmHg.

   Moreover, there was a significantly lower risk of cardiovascular disease for diabetics randomized to a SBP < 80 mmHg. Similar results were observed in the UKPDS 38 study (27),which showed that diabetics with better BP control (144/82 mmHg) had a higher reduction of cardiovascular risk than those less controlled (154/87 mmHg). In elderly hypertensives, a higher morbidity and mortality could not be demonstrated with a DBP below 80 mmHg. (3) A reduction in BP of 10/5 mmHg (SBP/DBP) is equivalent to a decrease of 10 cardiovascular events / 1000 patients per year, whereas a greater reduction of 20/10 mmHg may reduce the risk in 17 events / 1000 patients per year.

   In 1998, a survey was performed on 495 physicians from different specialties concerning diverse aspects of hypertension. (28) It was surprising that 74% were firmly against the use of fixed combinations in antihypertensive treatment, but only 29% were able to ground their decision. Even more surprising was the fact that all the physicians surveyed acknowledged the excellent results of using a product containing hydrochlorothiazide + amiloride in fixed combination. This evidences rigidity in therapeutic attitudes and disregards advances in clinical research.

   Although personal experience is of great value, it is also limited. It should be remembered that any fixed combination available is a product of years of research in many centers, which have studied a number of possible doses before deciding which of them are more adequate. Moreover, before they become available, the approval of national and international regulating institutions is required.

   In summary, despite significant progress in the knowledge of the pathophysiology of hypertension, its treatment and research methodologies, at least 3 of every 4 patients are poorly controlled and have an excess of 18/12 mmHg in systolic and diastolic BP, respectively. The myth of monotherapy has come to an end, opening the way for combination therapy with two complementary drugs at low doses, in free associations or in fixed combinations; the latter have proved to be an excellent choice for initial treatment of hypertension because of their lower costs and better tolerance, which accounts for a higher patient-adherence to treatment. (29,30)

REFERENCES

1. The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. National Institute of Health. Arch Intern Med 1997; 157:2413-2444.

2. Guidelines Subcomittee. 1999 World Health Organization - International Society of Hypertension Guidelines for the Management of Hypertension. J Hypertension 1999; 17:151-183.

3. SHEP Cooperative Research Group: Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension: final results of the Sistolic Hypertension in the Elderly Program (SHEP). JAMA 1991; 265:3255-3264.

4. Du X, Cruickshank K, McNamee R, et al.: Case-controll study of stroke and the quality of hypertension control in North West England. Br Med J 1997; 314:272-276.

5. Lazarus JM, Bourgoignie JJ, Buckalew VM, et al.: for the Modification of diet in renal disease study group. Achievement and safety of a low blood pressure goal in chronic renal disease: the Modification of Diet in Renal Disease Study Group. Hypertension 1997; 29:641-650.

6. Krumholz HM, Parent EM, Tu N, et al.: Readmission after hospitalization for congestive heart failure among medicare beneficiaries. Arch Intern Med 1997; 157:99-104.

7. Neaton JD, Grimm RH, Prineas RJ, et al. for the Treatment of Mild Hypertension Study Research Group. Treatment of Mild Hypertension Study: final results. JAMA 1993; 270:713-724.

8. Nigro D, Vergottini J, Kuschnir E, y col.: Epidemiología de la hipertensión arterial en la Ciudad de Córdoba, Argentina. Rev Fed Arg Cardiol 1999; 28:69-75.

9. Colhoun HM, Dong W, Poulter NR. Blood pressure screening, management and control in England: results from the health survey for England 1994. J Hypertens 1998; 16:747-752.

10. Berlowitz DR, Ash AS, Hickey EC, et al.: Inadequate management of blood pressure in a hypertensive population. N Engl J Med 1998; 339:1957-1963.

11. Hosie D, et al.: Cardiomonitor Study. J Hum Hypertens 1995; 9(Suppl. 2):S15 (Abstract)

12. Sever PS. The heterogenity of hypertension. Eur Heart J 1999; 1(Suppl.1):L10-L13.

13. Zanchetti A. Contribution of fixed low-dose combination to initial therapy in hypertension. Eur Heart J 1999; 1(Suppl.1): L5-L9.

14. Jones JK, Gorkin L, Lian JF, et al. Discontinuation of and changes in treatment after start a new courses of antihypertensive drgus: a study of a United Kingdom population. Br Med J 1995; 311:293-295.

15. Zachetti A. Combination therapy in the treatment of hypertension: addresing the clinical issues. Int J Clin Practice 1997; 90(Suppl):44-51.

16. Hypertension Detection and Follow-up Program Cooperative Group. Five year findings of the Hypertension Detection and Follow-up Program. I. Reduction in mortality of persons with high blood pressure, including mild hypertension. J Am Med Assoc 1979; 242: 2362-2377.

17. The Management Commitee. The Australian Therapeutic Trial in Mild Hypertension. Lancet 1980; i: 1260-1267.

18. Medical Research Council Working Party. MRC trial of treatment of mild hypertension: principal results. Br Med J 1985; 291: 97-104.

19. Guidelines Sub-Comittee. 1993 Guidelines for the management of mild hypertension: memorandum from a World Health Organization/International Society of Hypertension meeting. J Hypertension 1993; 11:905-918.

20. Hansson L, Zanchetti A, Carruthers SG, et al. For the HOT Study Group. Effects of intensive blood pressure lowering and low dose aspirin in patients with hipertension: principal results of the Hypertension Optimal Treatment (HOT) randomized trial. Lancet 1998; 351:1755-1762.

21. Rodríguez PD, Kuznicki S, Contreras VF, y col.: Blood pressure control in patients assisted in hypertension clinics. J Hypertension 2000; 18(Suppl. 2):S30 (Abstract)

22. Mancia G, Grassi G. Rationale for the use of a fixed combination in the treatment of hypertension. Eur Heart J 1999; 1(Suppl.1):L14-L19.

23. Tatti P, Pahor M, Byington RP, et al.: Outcome results of the fosinopril versus amlodipine cardiovascular events randomized trial (FACET) in patients with hypertension and NIDDM. Diabetes Care 1998; 21:597-603.

24. Farnett L, Mathew CD, Linn WD, et al. The J-Curve phenomenon and the treatment of hypertension: is there a point beyond which pressure reduction is dangerous? JAMA 1991; 265:489-495.

25. Coope J, Warrender TS. Randomized trial of treatment of hypertension in elderly patients in primary care. Br Med J 1986; 293:1145-1151.

26. Staessen J, Bulpitt C, Clement D, et al.: Relation between mortality and treated blood pressure in elderly patients with hypertension: report of the European Working Party on High Blood Pressure in the Elderly. Br Med J 1989; 298:1552-1556.

27. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. Br Med J 1998; 317:703-713.

28. Villamil AS. Conferencia del Ex-Director. Consejo Argentino de Hipertensión Arterial (SAC). Pinamar, 15-17 de octubre de 1998.

29. Weber MA. Unsolved problems in treating hypertension: rationale for new approaches. Am J Hypertens 1998; 11:145S-149S.

30. Kaplan NM. Low-dose combination in the treatment of hypertension: Theory and practice. J Hum Hypertens 1999; 13:707-710.

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2nd Virtual Congress of Cardiology

Dr. Florencio Garófalo
Steering Committee
President
Dr. Raúl Bretal
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