Our results showed that, compared with placebo, perindopril significantly improved the 6-minute walking distance by more than 30 m on average. A 20-m change in this distance is regarded as the minimum clinically important change in physical performance in elderly people.20
The degree of improvement observed in our study is comparable to the improvement seen after 6 months of exercise.21,22
The use of perindopril in our study resulted in improved exercise capacity over the 20 weeks rather than merely arresting decline. The absence of practice runs for the 6-minute walking test was unlikely to have affected the results, because any learning effect would have occurred in both the treatment and the placebo groups. Perindopril was well tolerated, as evidenced by similar dropout rates in the 2 groups. The dropout rate was lower than the anticipated 35%, which thereby reduced the need for recruitment from 146 to 130 participants in order to achieve our target sample of 94 participants to complete the study. Reports of cough may have led to some loss of randomization integrity; however, our analysis that excluded those with a cough still showed a significant improvement in the 6-minute walking distance in the perindopril group relative to the placebo group.
The improvement in exercise capacity was associated with a significant impact on health-related quality of life. Although the mean score for part 1 of the EQ-5D deteriorated over time in the placebo group by more than the minimal clinically important difference of 0.074,9
quality of life was maintained in the perindopril group. A fall in the EQ-5D score of 0.05 has been found to be associated with an increase in 5-year mortality.23
The improvement in the EQ-5D score in the perindopril group was not matched by a similar improvement in the EQ-5D visual analogue scale, however. This is in keeping with findings from other studies that found the EQ-5D visual analogue scale to be less sensitive to change than part 1 of the EQ-5D.24
We also found no effect of perindopril on the Nottingham Extended Activities of Daily Living scores. Even studies of exercise involving elderly people have shown no benefit using questionnaires on self-reported function and disability.25
Many physicians are concerned that ACE inhibitors may aggravate the risk of falls in elderly people by causing postural hypotension. Interestingly, we found a trend toward a reduction in the number of falls in the perindopril group relative to the placebo group over the study period. However, we excluded patients with symptomatic hypotension. Although it is possible that ACE inhibitors may reduce falls through improvement in physical function, studies specifically designed to evaluate this are required.
The positive influence of ACE inhibition on physical function in elderly people may be due to a number of potential mechanisms. ACE inhibitors increase nitric oxide production.1
Nitric oxide has been found to have a facilitatory action on the contractility of skeletal muscle at physiologic pressures of oxygen and to increase the number of sarcomeres and walking speed.26–28
A cross-sectional study involving elderly people without heart failure found that those taking an ACE inhibitor had increased muscle bulk compared with those taking another antihypertensive agent.29
In another study, ACE inhibition in patients with congestive heart failure was associated with increased exercise capacity and a shift in type of muscle fibre from type II to type I.30
Our findings of an increase in exercise capacity may also reflect a shift toward type I muscle fibre.
A direct influence of ACE inhibitors on cardiac function cannot be ruled out. In a randomized placebo-controlled trial, the ACE inhibitor ramipril was found to reduce left ventricular mass and preserve left ventricular function in patients without left ventricular systolic dysfunction.31
In the early stages of cardiac pressure overload, skeletal muscle dysfunction develops, and ACE inhibitors prevent this mainly by limiting the loss of cross bridges.32
A similar action of ACE inhibitors on skeletal-muscle cross bridges in elderly people may explain our results. It has been shown that cardiovascular problems are associated with poor physical function.33
ACE inhibitors may improve physical function by improving vascular function. Walking distance was found to improve in patients with peripheral vascular disease given ramipril.34
We conducted a post-hoc subgroup analysis of major baseline factors that could affect the change in 6-minute walking distance between the 2 groups. Although the results of this analysis showed that participants under 80 years of age and those with peripheral vascular disease tended to show more benefit from perindopril than their counterparts (), this should be inferred with caution and only considered as hypothesis generating.
The outcome measures used in our study reflect the demands of everyday life in elderly people. Our study is limited by the fact that only about one-quarter of the patients screened were eligible for inclusion in the study. However, because more than 46% of those not eligible were already receiving an ACE inhibitor or an angiotensin II receptor blocker, our findings may be generalizable to a larger population. The fact that only 20% of those eligible participated in the trial is not unusual in the population studied.35
Another limitation is that, although our study was powered to detect a 20-m change in 6-minute walking distance, it was probably too small to detect significant differences in other outcome measures. Also, for the secondary outcome measures, we did not carry out adjustments for multiple testing because there is no agreement as to the best way of achieving this for outcomes that are related to each other.