The safety of antihypertensive drugs - results of a long term surveillance study

The side effects of antihypertensive drugs were monitored in 5485 patients who were randomly assigned to Stepped Care in the community based Hypertension Detection and Follow-up Program (HDFP). The analysis included data from 3844 patients who were not taking antihypertensive medication at entry into the study and who presented regularly at 1 of the 14 clinical centres during the 5-year follow-up period .

The incidence of side effects requiring drug withdrawal

32.7% of the active participants experienced ~ 1 adverse reaction which caused the discontinuation of 1 or more drugs in the treatment regimen. 40% of these patients experienced > 1 side effect and the side effects were definite or probable, and possible in 9.3% and 23.4% of the patients, respectively. The definite or probable side effects occurred in 236 subjects with mild hypertension, 80 with moderate hypertension and 43 with severe hypertension. The largest number of total side effects and probable + definite side effects caused by drugs other than hydralazine and severe enough to cause the withdrawal of treatment occurred in the 50- to 59-year -old age group. The greatest incidence of hydralazine-induced reactions was in the 40- to 49-year-old age group and for all drugs the lowest number of total side effects and probable + definite side effects occurred in the 60- to 69-year-old age group. the frequency of most individual adverse dru~ reactions was also lowest in the latter age group. The incidence of total side effects (definite + probable + possible) in those aged 60 to 69, 50 to 59,40 to 49 and 30 to 39 years was 26.6%, 35.1%, 34.8% and 31 .9%, respectively.

A greater number of white men and women discontinued treatment because of side effects than black men and women but in all 4 race-sex groups the number of patients in whom treatment was withdrawn decreased over the 5-year period. No deaths were associated with drug-induced side effects and only 23 individuals were hospitalised for suspected drug-related events while 3% required outpatient treatment other than drug withdrawal. 14 hospital admissions were associated with chlorthalidone , 7 with reserpine , 1 with methyldopa and 1 with propranolol.

The nature of the side effects reported The side effects experienced by patients were

generally consistent with those reported in the literature. Most were of a neuropsychiatric nature but events as severe as depression were relatively uncommon compared with the incidence of nonspecific Side effects such as tiredness and dizziness. Gastrointestinal side effects were also common but peptic ulcers and bleeding from the gastrointestinal tract were not reported frequently . Electrolyte imbalance was the most common metabolic disorder requiring discontinuation of treatment, and dry mouth and nasal stuffiness were the commonest respiratory complaints .

Chlorthalidone, reserpine and methyldopa were the most frequently prescribed antihypertensives in the study. An analysis ot the incidence of selected side effects resulting in discontinuation of these drugs revealed that liver abnormalities and lethargy/ drowsiness were more frequent with methyldopa, and hypotension/orthostasis , peptic ulcer I gastrointestinat tract bleeding, nasal stuffiness , depression and nightmares occurred more frequently in reserpine reCipients . The side effects which were more common in the chlorthalidone group than in the other 2 groups induded: minor gastrointes tinal etfects , arthritisj arthralgias, muscle cramping, dermatitis , dizziness, weakness , hypokalaemia, hypercalcaemia, gout/hyperuricaemia and diabetes/hyperglycaemia.

A total of 83% of the active male participants took specific antihypertensive drugs and stopped taking them because of possible, probable or definite sexual problems. 153 males (6 .9%) experienced impotence (the commonest sexual problem with all HDFP drugs) while 53 reported decreased libido and only 6 (including 5 taking guanethidine) reported retrograde ejaculation . 10.8% of guanethidine reCipients experienced sexual problems compared with approximately 5% of patients taking chlorthalidone , reserpine or methyldopa.

The safety of antihypertensive therapy The HDFP study does not allow for a comparison

of the side effects of the drugs with those of placebo However, the study population is the largest ' .. . to date from which detailed drug surveillance data are available ' . Further , the side effects recorded were only those which required discontinuation of drug treatment and 'the frequency of possible drug side effects severe enough to cause discontinuation of drug therapy in the H DFP is consistent with clinical experience in the treatment of hypertension'.

In conclusion. ' .. . the HDFP data, which have previously demonstrated the beneficial effects of vigorous antihypertensive treatment, also affirm the relative safety of antihypertensive therapy' .

Curb. J.o .. Borhani. NO. . Blaszkowski. TP . Z,mbald,. N .. Fa /,u. S et al .. Journal of the American Medical Association 253' 3263·3268 (14 Jun 1985)