Rationale for Low-Dose Combination Therapy in Cardiovascular Risk Management
Data from recent studies have reconfirmed the importance of aggressive blood pressure control in protecting hypertensive patients from target organ damage. However, surveys performed to assess the adequacy of hypertension control in the United States have demonstrated that only one quarter of hypertensive patients are controlled at a level of 140/90 mmHg. If the currently recommended goals of 130/ 85 mmHg are applied, the controlled number is much less. Thus, our current approaches to the management of hypertension are failing in the most fundamental goals of treating hypertension. It is therefore crucial that we reassess the currently recommended approaches to hypertension to determine what changes need to be made in order to improve control rates.
An exciting alternative to the stepped-care approach to the management of hypertension is the use of low-dose combination therapy as first-line treatment or much earlier in the course of treatment. The purpose of this chapter is to discuss reasons for poor control rates among hypertensive patients and to demonstrate that low-dose combination therapy may provide a solution to many of our current problems associated with inadequate blood pressure control.
Reasons for inadequate blood pressure control
Data from the National Health and Nutritional Examination Survey (NHANES) have demonstrated that only 27.6% of hypertensive patients in the United States have adequate blood pressure control when using 140/90 mmHg as the goal. If the goal for treating hypertension is lowered to 130/85 or 120/80 mmHg, as recommended by the Point National Committee, in their sixth report, particularly for patients with associated cardiovascular risk factors, the percentage of controlled patients is significantly lower — despite the availability of more than 70 drugs for the management of hypertension. Thus, it is clear that the vast majority of hypertensive patients are inadequately controlled for hypertension. It is therefore not surprising that our treatment has not achieved the predicted reduction in coronary artery disease. There are several factors that contribute to inadequate blood pressure control, which can be corrected by the selection of treatment in the management of hypertension.
Patient Compliance
Patient compliance remains the most important cause of inadequate blood pressure control. Recent surveys have demonstrated that at 1 yr, <30% of patients are still taking their antihypertensive medication. Although there are multiple factors that influence patient compliance, including education, socioeconomic status, and cost, the factors that are most important are side effect profile and convenience of dosing schedule.
Side Effect Profile
Rationale for the stepped-care approach
The stepped-care approach for the management of hypertension is currently the suggested and generally accepted approach to the management of hypertension, despite the fact that 50% or more of patients will not be controlled by nonpharmacologic treatment or step 1 of the stepped-care approach. The rationale for the stepped-care approach is based on the belief that compared with combination therapy, monotherapy is more convenient, better tolerated, less expensive, and allows more simple identification of side effects if they occur. These assumptions are not entirely correct.
First, several low-dose combination formulations are now available as a single pill taken once-a-day. This makes them no more or less convenient than monotherapy. Second, of the approx 50% of patients who respond to monotherapy, about 60-70% require the highest recommended dose to achieve control. Because side effects are dose dependent, these patients are at a greater risk of developing side effects. Patients taking low-dose combination agents may have equal or better blood pressure control with fewer side effects because complementary agents in combination will provide the desired blood pressure reduction at lower doses (because of the additive effect on blood pressure), but with few side effects because of the lower doses. Third, two-drug therapy may be the most expensive way of treating hypertension because it involves the cost of titration, two co-payments, two dispensing fees, and the cost of two drugs. High-dose monotherapy also may be expensive because of titration costs, laboratory testing, and visits for increased side effects, and if two tablets are required to achieve the desired dose, the cost is double (in most cases). Low-dose combination therapy requires less titration, one co-payment, one dispensing fee, and a drug price that is typically less than if the two components were used as separate agents. Also it should be remembered that the cost of treating hypertension is not simply the cost of the drug, but includes the cost of the office visits, laboratory testing, visits for adverse events, and costs associated with the consequences of poor compliance and the problems associated with unhappy patients. Finally, the side effects that are typically associated with our modern antihypertensive agents are usually drug specific. It is as simple to stop a combination agent drug because of an adverse event and use another drug as it is to stop monotherapy. Thus, the main reasons for advocating the stepped-care approach for the treatment of hypertension may not apply, particularly with the development of low-dose combination agents as an alternative form of treatment.
Table Low-Dose Combination Drugs for Hypertension
| Drug class | Approved for
initial therapy |
Trade name |
| Beta Adrenergic blockers/diuretics Bisoprolol fumarate (2.5, 5, or 10 mg)/hydrochlorothiazide | Bisoprolol (2.5 mg)/hydrochlorothiazide (6.25 mg) | Ziac |
| angiotensin-converting enzyme inhibitors/diuretics
Benazepril hydrochloride (5,10, or 20 mg)/hydrochlorothiazide (6.25,12.5 or 25 mg) |
Lotensin HCT | |
| Captopril (25 or 50 mg)/hydrochlorothiazide (12.5 mg) | Captopril (25 mg)/hydrochlorothiazide (15 mg) | Capozide |
| Enalapril maleate (5 or 10 mg)/ hydrochlorothiazide (12.5 or 25 mg) | Vaseretic | |
| Lisinopril (10 or 20 mg)/hydrochlorothiazide (12.5 or 25 mg) | Prinzide, Zestoretic | |
| Angiotensin II receptor antagonists/diuretics | ||
| Losartan potassium (50 mg)/hydrochlorothiazide (12.5 mg) | Hyzaar | |
| Valsartan (80 mg)/hydrochlorothiazide (12.5 mg) | Diovan/HCT | |
| Calcium channel blockers/angiotensin-converting enzyme inhibitors | ||
| Amlodipine besylate (2.5 or 5 mg)/ benazepril hydrochloride (10 or 20 mg) | Irbesartan (150/
300 mg) hydrochlorothiazide (12.5 mg) Avelide Lotrel |
|
| Diltiazem hydrochloride (180 mg)/ enalapril maleate (5 mg) | Teczem | |
| Felodipine (5 mg)/enalapril maleate (5mg) | Lexxel | |
| Verapamil hydrochloride (extended release) (180 or 240 mg)/ trandolapril (1, 2, or 4 mg) | Tarka | |
“hydrochlorothiazide, hydrochlorothiazide; angiotensin-converting enzyme, angiotensin-converting enzyme.
Benefits of low-dose combination therapy
Cost of treating hypertension
The true cost of treating hypertension is not simply the cost of the antihypertensive medication but, rather, includes the costs of office visits, laboratory tests, office visits to deal with adverse events, the cost of poor patient compliance, and the mortality and morbidity associated with inadequate blood pressure control. Multiple office visits for titration to achieve adequate blood pressure control are frequently associated with significant cost in the management of hypertension. Similarly, drugs that require multiple laboratory tests to assess electrolytes and metabolic parameters may also be associated with significant cost. The costs associated with high-dose monotherapy may frequently be higher than realized. The use of high-dose monotherapy have the costs associated with titration, the potential of side effects associated with high-dose therapy, and frequently the cost of two tablets or capsules, which will double the treatment cost. Multiple drug therapy is also quite expensive because it includes the cost of two agents, two copayments, and two dispensing fees, as well as the costs of titration. Low-dose combination therapy is frequently less expensive than multiple drug therapy, requires only one copayment and one dispensing fee, and often requires fewer office visits to achieve adequate blood pressure control. Although it is generally believed that the cost of using combination therapy is higher than any other form of antihypertensive therapy, when carefully compared to other modalities of treatment, it frequently may be cheaper.
Outcome data
There are now several studies indicating that the protective effect of low-dose combination therapy may be greater than that seen with higher-dose monotherapy. This is probably related to the fact that lower blood pressures are achieved with combination therapy than with monotherapy, and that blood pressures have a significant protective effect in terms of cardiovascular outcome. The Hypertension Optimal Treatment study demonstrated that patients in the <80 mmHg group had a lower cardiovascular mortality than patients in the <90 mmHg group. This was particularly true in the diabetic patients. Perhaps the most important data derived from the Hypertension Optimal Treatment study is that when guided by a protocol, physicians can achieve adequate blood pressure control. The second most important piece of information is that although adequate blood pressure control was achieved, it was extremely difficult to achieve it with a single drug, and between two thirds and three quarters of the patients in this study required two or more antihypertensive drugs to achieve the target blood pressure.
Data from the Fosinopril Versus Amlodipine Cardiovascular Events Randomized Trial demonstrated that diabetic hypertensive patients treated with an angiotensin-converting enzyme inhibitor had fewer cardiovascular events than those patients treated with a calcium channel blocker. However, the patients treated with a combination of an angiotensin-converting enzyme inhibitor and a calcium channel blocker had fewer cardiovascular events than those treated with the angiotensin-converting enzyme inhibitor alone. This finding would suggest that angiotensin-converting enzyme inhibitors are indicated in diabetic hypertensive patients and that they have a protective effect. However, the combination of an angiotensin-converting enzyme inhibitor and a calcium channel blocker, probably as a result of the lower blood pressures, have an even greater protective effect on cardiovascular outcome than angiotensin-converting enzyme inhibitors alone. In a study comparing the renoprotective effects of an angiotensin-converting enzyme inhibitor as monotherapy to a combination of an angiotensin-converting enzyme inhibitor and a calcium channel blocker in patients with diabetic nephropathy, it was shown that the angiotensin-converting enzyme inhibitor as monotherapy had a protective effect on the kidney and reduced proteinuria, and that the combination of the angiotensin-converting enzyme inhibitor and calcium channel blockers had an even greater renoprotective effect with greater reductions in proteinuria. This further reduction in proteinuria is also probably related to the great blood pressure reduction seen in the patients with combination therapy.
There are thus multiple benefits to low dose combination therapy which may simplify the treatment of hypertension and provide greater blood pressure control.
Low-dose combination drug armamentarium
There are multiple low-dose combination agents available for use in hypertensive patients, including complementary drugs. To achieve a first-line indication in the treatment of hypertension, low-dose combination agents have to demonstrate in studies that they are more effective in reducing blood pressure than each of the components and that they have a side effect profile that is better than each of the component drugs. All available low-dose combination agents are more effective in reducing blood pressure than each of their component agents. However, most of the available combination agents (with the exception of bisoprolol/hydrochlorothiazide and captopril/hydrochlorothiazide) have been given a second-line indication only because they have a side effect profile similar to one of their respective component agents even if they are better than the second component agent. For example, with a combination of an angiotensin-converting enzyme inhibitor and a calcium channel blocker, the combination generally has a side effect profile slightly better than that of the calcium channel blocker because of a lower incidence of peripheral edema, but has a side effect profile similar to the angiotensin-converting enzyme inhibitor (because cough is not a dose-dependent side effect) and, thus, has been given a second-line indication. Low-dose combination drugs should be distinguished from “fixed dose” combination drugs, which combine two agents at each of their highest recommended doses in one tablet for convenience. This usually does not have the desired impact on the side effect profile because higher doses are included in these combinations. Low-dose combination drugs produce additive hypotensive effects, but because they comprise submaximum dose agents, the side effect profile is frequently much better than that seen with higher doses of monotherapy.
Conclusion
For many years, combination therapy was considered an option only late in the course of the management of hypertension. The current approach to the management of hypertension has clearly not been as effective as anticipated. The anticipated reduction in the incidence of coronary artery disease among hypertensive patients has not been seen. Also, the control rates of hypertensive patients, as demonstrated by NHANES, are disturbingly low. For these reasons, it is important that alternative modalities for the treatment of hypertension be considered. Low-dose combination therapy provides a very attractive choice either for first-line treatment in hypertension or for earlier use in the course of treating hypertensive patients. In addition, it may provide a means of improving efficacy, increasing patient compliance, and perhaps improving control rates among hypertensive patients. And, improved control rates may result in greater reductions in coronary artery disease disease among hypertensive patients.
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