ORLANDO – The ACE inhibitor ramipril boosted both walking ability and quality of life in patients with peripheral arterial disease in a double-blind, randomized trial.
This is the second randomized, placebo-controlled, double-blind study to show such effects, so it appears that the benefits are real.
Dr. Anna A. Ahimastos
And there’s more good news: "The magnitude of these effects is greater than that reported for conventional medical therapies," Dr. Anna A. Ahimastos observed when presenting the study findings at the annual scientific sessions of the American Heart Association.
She reported on 343 patients with peripheral arterial disease (PAD) who were randomized to 24 weeks of ramipril at 10 mg once daily or placebo. They averaged 65 years of age, 80% were men, the baseline ankle-brachial index was 0.56, and 36% had diabetes.
At 24 weeks, the average pain-free walking time (PFWT) in the ramipril group had increased by 87%, compared with a baseline of 131 seconds. The maximum walk time (MWT) improved by 139% from a baseline of 229 seconds. This corresponded to a clinically meaningful 172-meter increase in walking distance on a standardized treadmill test conducted at a speed of 3.2 km/hr and a 12% gradient, according to Dr. Ahimastos of the Baker IDI Heart and Diabetes Institute at Alfred Hospital in Melbourne.
In contrast, both PFWT and MWT decreased modestly over the course of 24 weeks in the control group.
A finding of particular importance in this impaired population with PAD was the documented improvement in quality of life that accompanied 24 weeks of ramipril, she continued. Daily functional capacity as measured by the WIQ (Walking Impairment Questionnaire) score domains of walking distance, speed, and stair climbing improved by 184%-213%. Scores on the SF-36 (36-Item Short Form) physical function component showed a significant 7% improvement from a baseline average of 38.5.
Results of this study are consistent with those of an earlier randomized, double-blind pilot study that Dr. Ahimastos and coworkers conducted in 40 patients (Ann. Intern. Med. 2006;144: 660-4).
Audience members who have grown accustomed to negative clinical trials being reported for PAD were enthusiastic at the prospect of finally gaining an additional effective medical therapy for this difficult condition.
The pilot study showed average gains of 164% in PFWT and 243% in MWT with 24 weeks of ramipril, a magnitude of benefit roughly twice that seen in the new, much larger trial. This is probably because the pilot study employed quite restrictive inclusion criteria, whereas the new study included a broader spectrum of PAD patients, including those with diabetes and with aortoiliac or infrainguinal disease.
Outcomes in the two randomized trials of ramipril for PAD – gains of 87%-164% in PFWT and 139%-243% in MWT – compare favorably with the results of placebo-controlled studies of conventional therapies. The phosphodiesterase-3 inhibitor cilostazol has shown 32%-82% improvements in PFWT and MWT. Pentoxifylline, another phosphodiesterase inhibitor, produced a 12% gain in MWT. And exercise training has shown a 150% improvement in both MWT and PFWT. However, the compliance rate with exercise is quite low in the PAD population, she noted.
Audience members who have grown accustomed to negative clinical trials being reported for PAD were enthusiastic at the prospect of finally gaining an additional effective medical therapy for this difficult condition. And they were curious as to Dr. Ahimastos’s thoughts on the mechanism of benefit.
She replied that at this point she can only speculate, since clinical trials don’t provide answers regarding mechanisms and the data from the new study were unblinded only the week prior to her presentation. She noted that ACE inhibitors have antiangiogenic and vasodilatory effects. The enhanced nitric oxide release and the drugs’ effects on bradykinin might also be relevant.
The improvement in walking doesn’t appear to stem from ramipril’s blood pressure–lowering effect, however, as the blood pressure reductions were minimal – less than 3 mm Hg in both systolic and diastolic blood pressure – and the degree of blood pressure reduction in individual patients didn’t correlate with their magnitude of walking improvement.
She and her colleagues don’t know whether angiotensin-receptor blockers would have similar clinical benefits on walking in PAD patients. That will prove difficult to study. For ethical reasons, future clinical trials are unlikely, as there is now evidence-based agreement among experts that patients with PAD should be on an ACE inhibitor or ARB anyway for cardiovascular protection.
The study was funded by Australia’s National Heart Foundation. Dr. Ahimastos declared having no financial conflicts.