Neither atenolol or nifedipine alone adversely affected walking distance but the combination decreased walking distance in intermittent claudication
ACP J Club. 1992 Mar-April;116:43. doi:10.7326/ACPJC-1992-116-2-043
Solomon SA, Ramsay LE, Yeo WW, Parnell L, Morris-Jones W. β Blockade and intermittent claudication: placebo controlled trial of atenolol and nifedipine and their combination. BMJ. 1991 Nov 2;303:1100-4.
To evaluate the effects of atenolol and nifedipine, alone and in combination, on walking performance and foot temperature of patients with intermittent claudication.
Randomized, placebo-controlled, double-blind crossover trial.
49 patients (82% men) with stable intermittent claudication lasting ≥ 6 months and occurring in ≤ 500 m of walking, with peripheral arterial disease confirmed by an ankle-to-brachial systolic pressure index < 0.9 by Doppler ultrasonography at rest, and who did not meet any exclusion criteria, were recruited. Mean duration of claudication was 32 months. 20 patients had angina and 10 had hypertension. 3 patients withdrew after randomization.
After a 4-week placebo run-in period, patients received atenolol, 50 mg; nifedipine, 20 mg; the 2 drugs combined; or placebo, all twice daily for 4 weeks, in a randomly allocated sequence. There were no washout intervals.
Main outcome measures
A constant-lead treadmill protocol was used to measure claudication and walking distances. Arm blood pressure and skin temperature of the plantar aspect of both big toes were also measured.
The 3 drug regimens did not differ from one another or from placebo in their effect on claudication distance, irrespective of the severity of claudication. Atenolol and nifedipine did not lead to reductions in maximal walking distance (reductions were 2%, 95% CI -4% to 8% and 4%, CI -3% to 10%, respectively). The combination of atenolol and nifedipine reduced maximal walking distance by 9% (CI 3% to 15%, P < 0.003); however, no drug therapy adversely affected perceived difficulty in walking. The combination drug therapy caused a slight decrease in foot skin temperature compared with placebo, by 1.1°C (CI 0% to 2.2%, P = 0.05) for the worse limb, and by 0.9°C (CI -0.2% to 1.9%, P > 0.05) for the better limb. All active treatments reduced systolic and diastolic blood pressure compared with placebo, and the combination treatment was more effective than either drug alone.
Neither atenolol nor nifedipine alone adversely affected walking distance in patients with intermittent claudication, but the combination of the 2 drugs caused a decrease in walking distance.
Source of funding: ICI PLC (United Kingdom).
Address for article reprint: Professor L.E. Ramsay, Floor L, Department of Medicine and Pharmacology, Royal Hallamshire Hospital, Sheffield S10 2JF, United Kingdom.
The use of β-adrenergic blockers in patients with peripheral arterial disease remains controversial because of concerns about worsening claudication. Most studies have concluded that β-blockers do not adversely affect walking exercise performance or the symptoms of claudication in this group. Results of this study were similar with atenolol, in terms of treadmill exercise performance or subjective walking ability. In addition, the authors studied the vasodilator nifedipine and also found no changes in claudication severity. However, the combination of the 2 drugs did reduce maximal walking distance by 9%, but did not affect the onset of claudication. These changes in treadmill performance were not reflected by any change in subjective walking ability. Finally, 2 patients (4%) dropped out with worsening claudication while on drug therapy.
The authors conclude that atenolol and nifedipine are safe as single agents in patients with claudication, but they recommend avoiding the combination of the two drugs, as well as the use of β-adrenergic blockers with vasodilating properties. It is important to note that all study drugs reduced systemic blood pressure. Although changes in arm blood pressure were not directly correlated with the reduction in exercise performance, any drug or combination of drugs that lowers blood pressure to this extent may worsen claudication. Whether this is due to a local steal phenomenon (as the authors suggest) or to a decreased perfusion pressure (as reflected by a lower ankle pressure) leading to reduced muscle blood flow remains to be determined. Clinically, β-blockers and calcium antagonists are important and safe drugs for patients with peripheral arterial disease who also have a high prevalence of angina, silent ischemia, arrhythmias, and hypertension. Worsening claudication (a rare side effect) may not be unique to a particular class of cardiovascular drugs, but rather reflect reductions in peripheral blood flow in susceptible patients.
William R. Hiatt, MD
University of Colorado School of MedicineDenver, Colorado, USA
William R. Hiatt, MD
University of Colorado School of Medicine
Denver, Colorado, USA