Fixed-dose combination therapy in hypertension: cons.

The goal of antihypertensive therapy is to reduce the risk associated with blood pressure elevation. Although the choice of first-line drug therapy may exert some effects on different long-term cardiovascular endpoints, randomized clinical trials and meta-analyses demonstrated that blood pressure reduction per se is the primary determinant in primary and secondary prevention. Numerous analyses carried out over the last years have repeatedly shown that many patients require the combination of two or more drugs to reach the recommended level of blood pressure control. Within this context, combination therapy with separate agents or fixed-dose combination pills offers an attractive ability to lower blood pressure more quickly, decrease adverse effects and reach blood pressure target. It is not clear whether fixed combinations of antihypertensive agents in a single tablet provide a greater benefit than the corresponding components given separately. In other words, it is not clear if the use of fixed combinations translates into a clearly improved blood pressure control and cardiovascular prevention in clinical practice. Fixed-dose combinations may simplify the treatment regimen by reducing the number of pills and may be attractive for many hypertensive patients. However, single-pill (fixed) drug combinations have some disadvantages: (i) branded fixed combinations may be more expensive than equivalent free combinations; (ii) the duration of action of individual components may not be equivalent, and this may not justify a single daily dosing of the combination; and (iii) the use of fixed combinations implies less flexibility in modifying the doses of individual components and the exposure of patients to unnecessary therapy. Moreover, should a patient develop side effects to one component, the entire combination should be discontinued and replaced by free drugs. The following three types of fixed-dose tablets have been recently proposed to give additional flexibility: (i) tablet manufactured so that each of the two drugs is placed at opposite ends of the tablet with a drug-free (inactive) layer placed in between; (ii) tablet with the combination of drugs at each end with the inactive zone in between; and (iii) tablet divided into discrete, separate segments (the two drugs are combined uniformly), which provides benefits for initial close titration and dosage adjustments. Currently, none of the fixed-dose tablets available on the market have these characteristics and, consequently, are unable to be broken to allow sufficient flexibility.