Quality of Life and Antihypertensive Drug Therapy

Joel Handler, MD

In This Article

Comparative Medication Studies and QOL

A comparative study of captopril 50 mg b.i.d. compared with methylodopa 500 mg b.i.d. and propranolol 80 mg b.i.d. was undertaken many years ago to monitor QOL over 6 months with these medications.[12] To no one's surprise, the study reported that captopril significantly outperformed the other two drugs, especially methyldopa, with regard to QOL measures. The study demonstrated that QOL could be successfully assessed by valid psychosocial measures and that significant drug-related QOL differences do exist. This study was criticized since it was well known that there were side effects to the relatively large doses of methyldopa and propranolol that were used in the study. Subsequent studies reported that while captopril significantly outperformed methyldopa or propranolol in terms of adverse effects, there was little difference with this agent when compared with atenolol, nifedipine, or amlodipine.[13,14] These QOL studies did show that the use of cardioselective ß blockers, like atenolol, resulted in fewer side effects than first-generation ß blockers such as propranolol, especially at higher dosages.

The angiotensin receptor blockers (ARBs), which were introduced for clinical use in the United States in 1995, were not tested in TOMHS. In a large review of drug tolerability comparing losartan and hydrochlorothiazide (HCTZ), total adverse experiences were comparable.[15] In patients with hypertension who received losartan or HCTZ, there were actually fewer adverse experiences with patients on either of these agents than patients on placebo.[16] The most frequent ARB adverse effects include dizziness and headaches. Patients who drop out of the ARB arm of a trial generally do so because of these effects.

In small, controlled trials comparing low-dose HCTZ with placebo in patients with hypertension, no difference has been found with regard to urination, but fewer episodes of asthenia, weakness, dizziness, fatigue, and headache were noted in patients on HCTZ, compared with placebo.[16] There are, of course, some individuals, especially those with prostatic hypertrophy, who experience increased urination and frequency on diuretic therapy, but these symptoms are also often noted in middle-aged or older men without specific therapy.

In the Antihypertensive Treatment and Lipid Profile in a North of Sweden Efficacy Evaluation (ALPINE) study,[17] adverse effects on HCTZ were significantly greater than those on candesartan, an ARB. This study, however, did not compare HCTZ to candesartan as monotherapies since 84% of patients on HCTZ were on a fairly high mean dosage of 68 mg of atenolol as an add-on agent (Figure 5) and 71% of patients in the candesartan group were on a fairly low mean dose of 3 mg of felodipine. It is possible to conclude that this difference in adverse effects may have been due at least in part to the relatively higher doses of the add-on agent.

Antihypertensive Treatment and Lipid Profile in a North of Sweden Efficacy Evaluation (ALPINE study). Eighty-four percent of the HCTZ arm patients were on a mean add-on dose of atenolol 68 mg and 71% of the candesartan (Cand) arm patients were on a mean dose of felodipine 3 mg. HCTZ=hydrochlorothiazide. Reprinted with permission from J Hypertens. 2003;21:1563-1574.[17]

An important concept is that of dose plateau relationships and efficacy compared with side effects. Figure 6 illustrates that as the dose of a drug is increased, there is declining additional efficacy -- or in the case of an antihypertensive agent, BP-lower-ing ability -- compared with increasing side effects. A small, earlier study had shown that the dose-pla-teau relationship for atenolol generally flattens out at approximately 25 mg.[18] In a combination drug treatment regime, therefore, it would seem appropriate to use 25-50 mg of atenolol. If patients still do not respond, the dosage can be increased to 100 mg, which is the usual top dose in the clinical trials. Twenty-five mg of HCTZ is probably at the elbow point of this curve. ACE inhibitors are somewhat different. Cough as a side effect occurs at low doses, as well as at high doses. The concept of efficacy compared with side effects provides the rationale for the modern drug treatment philosophy: use low dosages in combination to get maximum efficacy, improve tolerability, and reduce side effects.

Conceptual dose efficacy and dose side effect relationships for antihypertensive drugs.