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Abstract

  1. Top of page
  2. Abstract
  3. WHY ARE WE NOT CONTROLLING BLOOD PRESSURE?
  4. HOW CAN WE OPTIMIZE PATIENT COMPLIANCE?
  5. Side Effects
  6. Convenience of Dosing
  7. Early Control of Blood Pressure
  8. Polypharmacy
  9. Cost and Socioeconomic Status
  10. Patient Involvement in Their Treatment
  11. COMPLIANCE IN ELDERLY HYPERTENSIVE PATIENTS
  12. Benefits of Low-Dose Combination Therapy
  13. Conclusion
  14. References

The primary goal in the treatment of hypertension is to reduce the incidence of cardiovascular events in hypertensive patients. Studies performed to assess the impact of treating hypertension have revealed very disappointing reductions in the incidence of coronary heart disease. There are several reasons for these poor reductions in the incidence of cardiovascular disease; however, the most important is related to the fact that worldwide less than one quarter of hypertensive patients are adequately controlled for hypertension. Again, there are multiple reasons for these poor blood pressure (BP) control rates; however, most physicians would agree that patient compliance with their antihypertensive treatment is a major contributing factor. This is an area that we need to re focus on in our management of hypertensive patients. Issues such as safety, convenience, polypharmacy, cost, and education in the selection of antihypertensive agents are all critically important issues in the treatment of hypertensive patients. In addition, the level of patient involvement in their treatment seems to be essential in obtaining goal BP. Newer approaches to the management of hypertension such as earlier control of BP and the more aggressive use of low-dose combination therapy as first-line treatment of hypertension also need to be considered in our effort to improve BP control rates. Achieving goal BP in hypertensive patients is one of the most important clinical dilemmas facing physicians. There is little doubt that an improvement in control rates will result in substantial reductions in cardiovascular disease.

Several recent, long-term outcome studies have clearly demonstrated the benefit of blood pressure reduction on reducing cardiovascular disease. Moreover, these studies have shown that lower blood pressures are associated with greater reductions in cardiovascular disease, particularly in diabetic patients.1,2 Despite these findings, studies from the National Health and Nutritional Examination Survey (NHANES)3 and from the World Health Organization4 have indicated that less than one quarter of hypertensives worldwide are controlled for high blood pressure at the goal of 140/90 mm Hg.5 Since inadequately controlled hypertension remains a risk factor for coronary artery disease, these poor blood pressure control rates may contribute to the disappointing reductions in coronary artery disease6,7 and the high incidence of congestive heart failure seen among hypertensive patients. Furthermore, the increasing incidence of end-stage renal failure seen among hypertensive patients may also be related to inadequately controlled hypertension. Thus, obtaining optimal blood pressure control in hypertensive patients remains the most important issue in the management of hypertension and is clearly the area that has to be addressed more vigorously in the next few years.

WHY ARE WE NOT CONTROLLING BLOOD PRESSURE?

  1. Top of page
  2. Abstract
  3. WHY ARE WE NOT CONTROLLING BLOOD PRESSURE?
  4. HOW CAN WE OPTIMIZE PATIENT COMPLIANCE?
  5. Side Effects
  6. Convenience of Dosing
  7. Early Control of Blood Pressure
  8. Polypharmacy
  9. Cost and Socioeconomic Status
  10. Patient Involvement in Their Treatment
  11. COMPLIANCE IN ELDERLY HYPERTENSIVE PATIENTS
  12. Benefits of Low-Dose Combination Therapy
  13. Conclusion
  14. References

Despite the fact that we have in excess of one hundred drugs (from nine pharmacologically different classes) for the treatment of hypertension and that billions of dollars (12 billion in the United States alone) are spent on the treatment of hypertension annually, blood pressure control is achieved in less than one quarter of hypertensive patients.3 There are multiple reasons for these poor blood pressure control rates, but one of the most important remains patient compliance.8,9 In a recent study8 performed in a group of patients who received free medical care in California, it was shown that after 1 year on antihypertensive treatment, fewer than one third of the patients were still taking their antihypertensive drugs, irrespective of the class of drug with which they were treated. In another survey of 37,643 patients with hypertension performed between October, 1992 and September, 1993 in the United Kingdom,10 it was reported that change of treatment or discontinuation of treatment occurred in 40%–50% of the patients within 6 months. Patient adherence to therapy must be improved if we are to impact blood pressure control. Other important areas that contribute to poor control rates, include:

  • 1
    A reluctance of physicians to titrate medications. In many instances physicians accept inadequate blood pressure control for various reasons including concern over increasing side effects (with increasing dose of medication), increased metabolic side effects, cost,11 and lack of conviction that lowering blood pressure, especially systolic blood pressure, will improve outcome.
  • 2
    Due to the multifactorial nature of hypertension, it is extremely difficult to achieve blood pressure control with monotherapy.12,13 Despite this, there is still resistance to the use of combination therapy in the management of hypertension.
  • 3
    The Joint National Committee5 and the World Health Organization4 (based on good studies) have indicated that adequate blood pressure con trol is <140/90 mm Hg but even lower in patients with diabetes, or renal disease. This lower optimal blood pressure goal has resulted in an even greater number of inadequately controlled hypertensives.

HOW CAN WE OPTIMIZE PATIENT COMPLIANCE?

  1. Top of page
  2. Abstract
  3. WHY ARE WE NOT CONTROLLING BLOOD PRESSURE?
  4. HOW CAN WE OPTIMIZE PATIENT COMPLIANCE?
  5. Side Effects
  6. Convenience of Dosing
  7. Early Control of Blood Pressure
  8. Polypharmacy
  9. Cost and Socioeconomic Status
  10. Patient Involvement in Their Treatment
  11. COMPLIANCE IN ELDERLY HYPERTENSIVE PATIENTS
  12. Benefits of Low-Dose Combination Therapy
  13. Conclusion
  14. References

Since patient compliance appears to be a very important contributor to poor control rates (in addition to poor physician adherence to goal levels), it is an area that requires more attention. There are several important factors that influence patient compliance that should be addressed.

Side Effects

  1. Top of page
  2. Abstract
  3. WHY ARE WE NOT CONTROLLING BLOOD PRESSURE?
  4. HOW CAN WE OPTIMIZE PATIENT COMPLIANCE?
  5. Side Effects
  6. Convenience of Dosing
  7. Early Control of Blood Pressure
  8. Polypharmacy
  9. Cost and Socioeconomic Status
  10. Patient Involvement in Their Treatment
  11. COMPLIANCE IN ELDERLY HYPERTENSIVE PATIENTS
  12. Benefits of Low-Dose Combination Therapy
  13. Conclusion
  14. References

Patient surveys, which have attempted to determine the reasons for poor patient compliance, have repeatedly demonstrated that side effects associated with antihypertensive drugs are important in determining compliance rates.8 The development of new pharmacologic agents, such as the angiotensin receptor blockers that are well tolerated, has demonstrated that the selection of drugs with more favorable side effect profiles results in improved compliance rates. Data from a large pharmacy database14 in the United States have shown that when assessing compliance rates at 1 year, patients treated with angiotensin receptor blockers had greater compliance rates than those treated with other classes of antihypertensive agents. These data were confirmed in a second study assessing compliance rates at 1 year.14

Dose dependent side effects are probably one of the important reasons for acceptance of inadequate blood pressure control by physicians. In many instances (especially in the elderly), a physician may have a treated patient who has not achieved blood pressure control. They are then faced with a dilemma, either increase the dose of the drug and risk the development of dose-dependent side effects, which may adversely affect patient compliance, or accept inadequate control and perhaps advocate more aggressive nonpharmacologic treatment. Physicians often accept inadequate control.11 Physician adherence to goal therapy is not a new problem and was the subject of concern more than 20 years ago.15

Use of Low-Dose Combination Therapy to Decrease Side Effects. Low-dose combination therapy may provide an effective alternative to first-line treatment of hypertensives, and may decrease side effects associated with antihypertensive agents.12 The concept of low-dose combination therapy is that the use of two complimentary antihypertensive agents, given in small doses, will enable blood pressure control to be achieved at lower doses of each of the component drugs but with fewer dose-dependent side effects. Studies have shown12,16–23 that low-dose combinations produce fewer adverse reactions than high-dose monotherapy (with the same drugs). Some combinations help to limit the side effects that may occur when one component is used. For example, less peripheral edema is noted with a combination of an angiotensin-converting enzyme (ACE) inhibitor and a calcium channel blocker than with a calcium channel blocker used as monotherapy at the same dose. The use of lower-dose combination therapies earlier in the treatment of hypertension may be one important change that can be made in our approach to the management of hypertension. In fact, the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI)5 suggested that the use of low-dose combination therapy was appropriate first-step treatment. In a recent study22 that required investigators to achieve a goal blood pressure, a majority of patients required between 2–4 drugs to achieve these goals.

Convenience of Dosing

  1. Top of page
  2. Abstract
  3. WHY ARE WE NOT CONTROLLING BLOOD PRESSURE?
  4. HOW CAN WE OPTIMIZE PATIENT COMPLIANCE?
  5. Side Effects
  6. Convenience of Dosing
  7. Early Control of Blood Pressure
  8. Polypharmacy
  9. Cost and Socioeconomic Status
  10. Patient Involvement in Their Treatment
  11. COMPLIANCE IN ELDERLY HYPERTENSIVE PATIENTS
  12. Benefits of Low-Dose Combination Therapy
  13. Conclusion
  14. References

Antihypertensive agents that are dosed once daily are taken more regularly than drugs that have to be taken more than twice daily.24 There is little reason to prescribe drugs that must be taken three times a day in a hypertensive patient. There are now many drugs available that can be safely and effectively given once daily. It is important for physicians to select agents that provide adequate blood pressure control over the entire 24-hour dosing interval. Several medications marketed as once-a-day agents tend to loose efficacy during the last few hours of the dosing interval.25 Loss of blood pressure control tends to coincide with the rapid increase in blood pressure during arousal from sleep,25 and the time during which the peak incidence of non-embolic stroke and myocardial infarction occurs.26 It is believed (but not proven) that optimal blood pressure control during this early morning period is desirable and that inadequate control during this time may result in a relative increase in cardiovascular disease.27,28 Duration of action can be clinically assessed simply by instructing patients to omit dosing on the morning of their clinic visit. If blood pressure remains controlled 24–26 hours post dosing then this is good evidence of once-a-day efficacy.

Early Control of Blood Pressure

  1. Top of page
  2. Abstract
  3. WHY ARE WE NOT CONTROLLING BLOOD PRESSURE?
  4. HOW CAN WE OPTIMIZE PATIENT COMPLIANCE?
  5. Side Effects
  6. Convenience of Dosing
  7. Early Control of Blood Pressure
  8. Polypharmacy
  9. Cost and Socioeconomic Status
  10. Patient Involvement in Their Treatment
  11. COMPLIANCE IN ELDERLY HYPERTENSIVE PATIENTS
  12. Benefits of Low-Dose Combination Therapy
  13. Conclusion
  14. References

The stepped care approach for the management of hypertension may require some time to achieve blood pressure control. Physicians have developed a level of comfort with managing hypertension in this fashion. However, if one drug is used and is ineffective and another medication added, blood pressure control may be delayed and patient compliance affected.

There are many potential patient and physician obstacles to blood pressure control (Figure 1). The longer it takes to control blood pressure the more likely it is the physician will accept inadequate blood pressure control. If the time to blood pressure control is shortened, the likelihood of achieving control is greater. One of the concerns that physicians have with more rapid blood pressure control is that it may result in side effects such as dizziness or hypotension. However, this does not seem to occur (unless the patient has significantly compromised ventricular function). In studies comparing low dose combinations as first-line therapy with higher-dose monotherapy, blood pressure reductions with the combination agent were greater than the monotherapies. There were no significant differences in side effects.19-22 It has been demonstrated that patients with lower blood pressures have an improvement in quality of life. Data from the Hypertension Optimal Treatment (HOT)29 study demonstrated that patients with the lowest blood pressures (in the <80 mm Hg group) had the greatest improvement in quality of life.

image

Figure 1. Opportunities for accepting inadequate blood pressure (BP) control. There are many obstacles (both patient and doctor) that physicians encounter from the point of diagnosis of hypertension (HTN) to the point of achieving BP control. Many of these obstacles result in physicians accepting inadequate BP control. To the extent that BP control is achieved earlier in the course of treating hypertensive patients (hatched box) we potentially eliminate some of their obstacles and are more likely to achieve control. HMO=health management organization; AE=adverse event

In a recent study30 it was demonstrated that one of the more important indicators of patient compliance in the second 6 months of antihypertensive treatment was the number of medication changes (and consequently the length of time to achieve blood pressure control) during the first 6 months of treatment (Figure 2). It appears that more rapid control of blood pressure with fewer changes in the treatment regimen has a positive psychologic effect on patients. If a patient is told that goal blood pressure is 120/80 mm Hg and the initial treatment fails to achieve this goal, they are likely to believe that the medication is not working and stop taking it. On the other hand if control is achieved more rapidly they are often impressed by the efficacy of the agent and thus tend to be more compliant. In addition, the cost associated with treatment may be diminished.31

image

Figure 2. Factors influencing patient compliance

Polypharmacy

  1. Top of page
  2. Abstract
  3. WHY ARE WE NOT CONTROLLING BLOOD PRESSURE?
  4. HOW CAN WE OPTIMIZE PATIENT COMPLIANCE?
  5. Side Effects
  6. Convenience of Dosing
  7. Early Control of Blood Pressure
  8. Polypharmacy
  9. Cost and Socioeconomic Status
  10. Patient Involvement in Their Treatment
  11. COMPLIANCE IN ELDERLY HYPERTENSIVE PATIENTS
  12. Benefits of Low-Dose Combination Therapy
  13. Conclusion
  14. References

There tends to be an inverse relationship between the number of drugs that a patient has to take and their adherence to a regimen. The reasons for this decrease in compliance are related to:

  • 1
    Cost—There is greater cost with multiple drugs.
  • 2
    Convenience—It is easier to forget to take multiple drugs.
  • 3
    Confusion—Patients often become confused by multiple drugs and frequently dose them incorrectly.

Combination therapy is often helpful in reducing some of these problems. There are now several combination agents available that require that one pill be taken once-daily. This frequently is more convenient and less confusing than multiple-drug therapy and in some instances may be less expensive.

Cost and Socioeconomic Status

  1. Top of page
  2. Abstract
  3. WHY ARE WE NOT CONTROLLING BLOOD PRESSURE?
  4. HOW CAN WE OPTIMIZE PATIENT COMPLIANCE?
  5. Side Effects
  6. Convenience of Dosing
  7. Early Control of Blood Pressure
  8. Polypharmacy
  9. Cost and Socioeconomic Status
  10. Patient Involvement in Their Treatment
  11. COMPLIANCE IN ELDERLY HYPERTENSIVE PATIENTS
  12. Benefits of Low-Dose Combination Therapy
  13. Conclusion
  14. References

Cost, socioeconomic status, and accessibility to medical care will influence patient compliance. These issues need to be carefully considered in the management of patients, and frequently pose a problem. The more recently introduced drugs and combinations tend to be more expensive. However, it should be stressed that the cost of treating hypertension should not simply be considered to be the cost of the drug. There are other factors that contribute to the cost of treating hypertension—cost of office visits, the cost of laboratory tests, as well as the costs of morbidity and mortality associated with failure to achieve goal blood pressure.

It should also be remembered that there are substantial costs associated with treatment discontinuation (for whatever reason) and prescription switching in the management of hypertension. A recent survey was performed in the United Kingdom to determine the resource costs arising from treatment discontinuation and prescription switching. The study was conducted over a 26-month period in newly diagnosed hypertensive patients who had been prescribed at least one antihypertensive agent belonging to one of the four hypertensive therapeutic classes (ACE inhibitors, β blockers, calcium channel antagonists, and diuretics). The analysis included a sample of 7741 patients and demonstrated that the health care costs arising from hospitalization and visits to primary care physicians where significantly higher in the patients who discontinued their medication than in those who continued their treatment. Moreover, the treatment cost for patients whose treatment was switched (including drug costs) was 20% more expensive than in patients who remained on their original treatment.31,32

Patient Education. Patient education is critical in the management of hypertension and yet is an area that is frequently neglected. Patients who have been educated (by doctors or nurses) and understand their disease process, the goal blood pressures, potential side effects associated with antihypertensive drugs (and the fact that drugs can be changed to improve on side effects), and the consequences of poor compliance and inadequate blood pressure control tend to be more compliant. In many instances it has been shown that patients who have stopped their medication believed that hypertension was a curable disease. With increasing demands on physicians' time it has become increasingly difficult for physicians to adequately educate patients. The use of nurse practitioners, nurses, social workers, and other paramedical staff in education and home monitoring of patients has proven to be important in this education process and may significantly improve patient compliance.

Patient Involvement in Their Treatment

  1. Top of page
  2. Abstract
  3. WHY ARE WE NOT CONTROLLING BLOOD PRESSURE?
  4. HOW CAN WE OPTIMIZE PATIENT COMPLIANCE?
  5. Side Effects
  6. Convenience of Dosing
  7. Early Control of Blood Pressure
  8. Polypharmacy
  9. Cost and Socioeconomic Status
  10. Patient Involvement in Their Treatment
  11. COMPLIANCE IN ELDERLY HYPERTENSIVE PATIENTS
  12. Benefits of Low-Dose Combination Therapy
  13. Conclusion
  14. References

Getting patients involved in their antihypertensive treatment may frequently influence compliance. The use of home blood pressure monitors will often get patients more interested and involved in their treatment. This may have a beneficial effect. It is essential that if home monitors are used the following factors are considered:

  • 1
    Patients obtain a reputable monitor. (Omron [Omron Healthcare, Vernon Hills, IL] and Sunbeam [Sunbeam Products, Maitland, FL] are the two systems that have been assessed by consumer reports during the past 2 years to be the most accurate systems.)
  • 2
    Physicians validate the patient's monitor to their own mercury sphygmomanometer.
  • 3
    Patients are taught how to correctly measure blood pressure (e.g., arm at level of the heart, 5-minute rest period in a seated position prior to measurement of blood pressure).
  • 4
    Patients are encouraged not to measure blood pres sure more than 2–3 times per week. Readings should be noted by the patients and brought to the physician. It is useful to have the patients monitor blood pressure in the morning and afternoon (at the same time in the morning or afternoon).
  • 5
    In reporting to their physicians, patients should not exclude the higher reading to avoid changes in treatment. (Some patients take multiple readings until they get a good one and then report that reading.)

If all of these factors are taken into consideration, home blood pressure monitoring can be helpful and should be considered in the treatment of hypertension. Once patients are involved in the monitoring of their disease process, they may become more compliant with their medication as the consequence of missing drug doses becomes apparent.

The benefits of diet, exercise, smoking cessation, and weight loss may also be more apparent to patients who are involved in their disease management and who are given reading materials and encouraged to discuss their progress.

COMPLIANCE IN ELDERLY HYPERTENSIVE PATIENTS

  1. Top of page
  2. Abstract
  3. WHY ARE WE NOT CONTROLLING BLOOD PRESSURE?
  4. HOW CAN WE OPTIMIZE PATIENT COMPLIANCE?
  5. Side Effects
  6. Convenience of Dosing
  7. Early Control of Blood Pressure
  8. Polypharmacy
  9. Cost and Socioeconomic Status
  10. Patient Involvement in Their Treatment
  11. COMPLIANCE IN ELDERLY HYPERTENSIVE PATIENTS
  12. Benefits of Low-Dose Combination Therapy
  13. Conclusion
  14. References

It is now well known that systolic hypertension, commonly seen in elderly patients, is a strong predictor of cardiovascular disease and that reduction of blood pressure in this patient subgroup is associated with reductions in cardiovascular disease.32,33 As a result, physicians are now diagnosing and treating systolic hypertension. However, controlling systolic blood pressure has proven to be even more difficult than controlling diastolic blood pressure, and in most instances combination therapy is required.34,35 Not surprisingly, all the factors previously discussed are especially apparent in the elderly hypertensive patient and must be carefully considered in the management of this patient group. It should be remembered that polypharmacy is more of a problem in the elderly, who frequently have several disease processes requiring treatment. Single-drug combination therapy is often useful. Pill splitting may be difficult for elderly patients and should be discouraged. Visual impairment in the elderly may also be important in drug compliance. Education and the use of support teams both in the clinic and in the patients' home environment may be important in achieving blood pressure control. The selection of well-tolerated drugs is particularly important in the management of elderly hypertensive patients.

Low-dose therapy may be useful in the management of elderly patients.35 In a recent study,36 elderly patients (age 65–85 years) with systolic blood pressures between 160–210 mm Hg were given the low-dose combination of perindopril (an ACE inhibitor) plus indapamide as first-line treatment following a run-in period of 4 weeks. A systolic blood pressure of <160 mm Hg was achieved in 83% of patients following 3 months of treatment and 80% had a systolic blood pressure of <160 mm Hg following 1 year of treatment. Of note, the proportion of adverse events related to drug treatment was 23% in patients treated with placebo and 20% in patients treated with the perindopril/indapamide combination.36 Excellent results have also been obtained with the use of small doses of a thiazide diuretic and a β blocker or thiazide diuretic and an angiotensin II receptor blocker.37

Benefits of Low-Dose Combination Therapy

  1. Top of page
  2. Abstract
  3. WHY ARE WE NOT CONTROLLING BLOOD PRESSURE?
  4. HOW CAN WE OPTIMIZE PATIENT COMPLIANCE?
  5. Side Effects
  6. Convenience of Dosing
  7. Early Control of Blood Pressure
  8. Polypharmacy
  9. Cost and Socioeconomic Status
  10. Patient Involvement in Their Treatment
  11. COMPLIANCE IN ELDERLY HYPERTENSIVE PATIENTS
  12. Benefits of Low-Dose Combination Therapy
  13. Conclusion
  14. References

The use of low-dose combination therapy may be particularly important in elderly patients for the following reasons:

  • 1
    Allows for greater efficacy in patients who are typically difficult to control.
  • 2
    There are fewer dose-dependent side effects in a group of patients who may be more sensitive to the side effects of antihypertensive agents.
  • 3
    Physicians are able to achieve blood pressure control with fewer drugs (simplifies treatment regimen).
  • 4
    Frequently, subscription plans such as Medicaid count a combination as a single drug, enabling patients to get an additional agent without added expense.

Conclusion

  1. Top of page
  2. Abstract
  3. WHY ARE WE NOT CONTROLLING BLOOD PRESSURE?
  4. HOW CAN WE OPTIMIZE PATIENT COMPLIANCE?
  5. Side Effects
  6. Convenience of Dosing
  7. Early Control of Blood Pressure
  8. Polypharmacy
  9. Cost and Socioeconomic Status
  10. Patient Involvement in Their Treatment
  11. COMPLIANCE IN ELDERLY HYPERTENSIVE PATIENTS
  12. Benefits of Low-Dose Combination Therapy
  13. Conclusion
  14. References

Patient compliance or adherence has been a major problem in the management of hypertension for as long as we have been treating this disease process. Although the development of drugs with more favorable side-effect profiles as well as the development of once-a-day agents has resulted in some improvement in patient compliance, it still remains an important issue in the management of hypertension. Physicians should refocus on issues that influence compliance in their management of this disease process. Many of the important issues influencing compliance can be corrected with the appropriate approach. Clearly the selection of well-tolerated drugs that can be dosed once daily is critical. The use of low-dose combination therapy as first-line treatment for a significant percentage of hypertensive patients may represent an important change in our management and may improve compliance rates. Achieving more rapid blood pressure control may also have some beneficial effects on patient compliance. In order to improve on the outcome in hypertensive patients, we will have to significantly improve patient, as well as physician, compliance.

References

  1. Top of page
  2. Abstract
  3. WHY ARE WE NOT CONTROLLING BLOOD PRESSURE?
  4. HOW CAN WE OPTIMIZE PATIENT COMPLIANCE?
  5. Side Effects
  6. Convenience of Dosing
  7. Early Control of Blood Pressure
  8. Polypharmacy
  9. Cost and Socioeconomic Status
  10. Patient Involvement in Their Treatment
  11. COMPLIANCE IN ELDERLY HYPERTENSIVE PATIENTS
  12. Benefits of Low-Dose Combination Therapy
  13. Conclusion
  14. References
  • 1
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    McCombs JS, Nichol M, Newman C, et al. The costs of interrupting antihypertensive therapy in a Medicaid population. Med Care. 1994;32:214226.
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  • 19
    Neutel JM, Rolf CN, Valentine SN, et al. Low-dose combination therapy as first-line treatment of mild-to-moderate hypertension: the efficacy and safety of bisoprolol/HCTZ versus amlodipine, enalapril, and placebo. Cardiovasc Rev Rep. 1996;71(11):19.
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    Kuschair E, Acura E, Sevilla D. Treatment of patients with essential hypertension: amlodipine 5mg/Benazepril 20mg compared with amlodipine 20mg and placebo. Clin Ther. 1996;18:612.
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    Messerli F, Frishman WH, Elliott WJ. Effects of verapamil and trandolapril in the management of hypertension. Trandolapril Study Group. Am J Hypertens. 1998;11(3 pt 1):322327.
  • 22
    Frishman WH, Bryzinski BS, Coulson LR. A multifactorial trial design to assess combination therapy in hypertension. Arch Intern Med. 1994;154:14631470.
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    Meyers M, Asmer R, Leenen F, et al. Fixed low-dose combination therapy in hypertension-a dose response study of peridopril and indapamide. J Hypertens. 2000;18:317325.
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    Sica DA. Fixed dose combination antihypertensive drugs. Do they have a role in rational therapy? Drugs. 1994;48(1):1624.
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    Neutel JM, Smith DHG, Ram CVS, et al. Comparison of bisoprolol vs. atenolol for systemic hypertension in four population groups (young, old, black and non-black) using ambulatory blood pressure monitoring. Am J Cardiol. 1993;72:4146.
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  • 29
    Willund I, Halling K, Ryden-Bergsten T, et al. Does lowering the blood pressure improve the mood? Quality-of-life results from the Hypertension Optimal Treatment (HOT) study. Blood Press. 1997;6(6):357364.
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    Caro JJ, Speckman JL, Salas M, et al. Effect of initial drug choice on persistence with antihypertensive therapy: the importance of actual practice data. CMAJ. 1999;160(1):4146.
  • 31
    Hughes D, McGuire A. The direct costs to the NHS of discontinuing and switching prescriptions for hypertension. J Hum Hypertens. 1998;12:533537.
  • 32
    Moser M. Clinical Management of Hypertension. 6th ed. Caddo , OK : Professional Communications, Inc.; 2002.
  • 33
    Chiasson JL, Gomis R, Hanefeld M, et al. The STOP-NIDDM Trial: an international study on the efficacy of an alpha-glucosidase inhibitor to prevent type 2 diabetes in a population with impaired glucose tolerance: rationale, design, and preliminary screening data. Study to Prevent Non-Insulin Dependent Diabetes Mellitus. Diabetes Care. 1998;10:17201725.
  • 34
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