Benefits of low-dose combination therapy
The concept behind low-dose combination therapy is to combine two complementary antihypertensive agents in order to achieve an additive effect on blood pressure reduction, but have fewer side effects because of the ability to achieve blood pressure control with small doses of each of the agents.
Table Advantages of Low-Dose Combination Therapy
| Effectively reduces blood pressure |
| Effective over 24 h with once-a-day dosing |
| Higher response rates |
| Fewer side effects |
| Fewer adverse metabolic effects |
| Less expensive than multiple-drug therapy |
Table Mean Changes in Diastolic blood pressure with a Low-Dose Combination vs Its Components”
| Treatment | Mean decrease in
diastolic blood pressure (mmHg) |
Response rate
(%) |
| Placebo | — | 15.8 |
| Amlodipine (5 mg) | 8.6 | 67.5 |
| Benazepril (20 mg) | 7.0 | 53.3 |
| Amlodipine (5 mg)/benazepril (20 mg) | 13.9 | 87.0 |
Efficacy
Studies using low-dose combination agents have demonstrated that the use of small doses of complementary antihypertensive agents results in additive reductions in blood pressure frequently greater than larger doses of the component agents. The greater efficacy occurs as a result of interruption of two or more physiologic mechanisms contributing to the increase in blood pressure, thus producing greater reduction in blood pressure than could be achieved with a more complete block (utilizing high-dose mono-therapy) of one pathway. Furthermore, because studies have shown that physicians are reluctant to titrate antihypertensive medication, agents that produce blood pressure control (with fewer side effects) early in the treatment of hypertension have a greater likelihood of achieving blood pressure control.
Response Rate
Only about 50% of hypertensive patients will respond to any particular class of antihypertensive agent. In some subgroups of hypertensive patients, response rates may be much lower than 50% with particular agents, e.g. angiotensin-converting enzyme inhibitors in African-American patients. Adding a second complementary agent significantly increases response to >75% and may equalize rseponse across various patient subgroups, as is seen when adding a small dose of diuretic to an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. The use of lower-dose combination drugs thus frequently simplifies the treatment of hypertension in that all subgroups are more likely to respond to these agents.
Adverse Events
Low-dose combination therapy provides the ability to achieve both safety and efficacy. Frequently, the doses of monotherapy that can be used are limited by an associated increase in dose-dependent side effects that has an adverse effect on efficacy. However, the side effect profile of many of the newer low-dose combination agents is at least equal to and sometimes better than that seen with placebo. For example, the side effect profile of the combination of an angiotensin-converting enzyme inhibitor and a calcium channel blocker (calcium channel blocker) is frequently better than similar doses of each of the components used as monotherapy. Peripheral edema is a common side effect of calcium channel blockers and occurs as a result of the vasodilatation produced by calcium channel blockers, which occurs predominantly in the arterial system, with very little effect on the venous system. These result in increased capillary hydrostatic pressure and the development of a capillary leak syndrome with resultant peripheral edema. angiotensin-converting enzyme inhibitors cause vasodilatation in both the arterial and venous systems. Thus, adding an angiotensin-converting enzyme inhibitor to a calcium channel blocker results in venous dilatation. The venous dilatation decreases the pressure in the capillary bed, and the combination results in less edema than does a similar dose of the calcium channel blocker given as monotherapy.
Interestingly, cough is the one antihypertensive-related side effect that is not dose dependent. Therefore, the incidence of cough is similar in the combination of an angiotensin-converting enzyme inhibitor and a calcium channel blocker as it is when an angiotensin-converting enzyme inhibitor is given alone as monotherapy.
Duration of Action
Studies using ambulatory blood pressure monitoring have demonstrated that low-dose combination agents maintain adequate blood pressure control throughout the dosing interval if the correct agents are utilized in the combination. The reductions in blood pressure will parallel each of the component agents throughout the dosing interval at a consistently lower blood pressure.
Cost
The issue of cost is much more complex with combination therapy than initially realized. It is possible that, in some instances, low-dose combination therapy may be cheaper than high-dose monotherapy or multiple dose therapy.
Metabolic Effects
Several studies have shown that antihypertensive drug-related metabolic effects (e.g., hypokalemia, hypoglycemia, and increased low-density lipoprotein cholesterol) are also dose dependent. When given in small doses, drugs such as diuretics and β-blockers may have a slightly beneficial effect on glucose and lipid metabolism, even though at higher doses they may have negative effects on these metabolic parameters.
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