Bisoprolol is Effective in Reducing Ischemic Burden and Peaks – TIBBS: A Double-blind Randomized Multicenter Trial
Introduction
Transient myocardial ischemia has important prognostic implications in patients with chronic stable angina and thus needs optimal treatment. Beta-blockers and calcium channel-blockers are used to treat transient myocardial ischemia in chronic stable angina as they may improve the load conditions and oxygen supply.
However, the benefits of beta-blockers and calcium channel-blockers in reducing transient myocardial ischemia have been only demonstrated in small studies. Moreover, the comparative efficacy of these agents in transient myocardial ischemia is unknown.
Bisoprolol is a once-daily cardio-selective beta-blocker and its effects last for 24 hours. However, no large study has compared the efficacy of bisoprolol with that of nifedipine, a commonly used twice-daily calcium channel-blocker, in patients with chronic stable angina.
Aims
This 2-arm double-blind randomized clinical trial by von Arnim1 aimed to compare the efficacy of bisoprolol and nifedipine in chronic stable angina patients with demonstrated transient myocardial ischemia in terms of reduction in the number and duration of transient ischemic episodes, including the morning peaks of ischemia.
Methods
This multicenter study was conducted in 30 European centers between 1991 and 1993, and was entitled the “Total Ischemic Burden Bisoprolol Study (TIBBS).” Males with typical clinical history and exercise stress test-based evidence of coronary artery disease (CAD), and females with additional angiographic or thallium scintigraphy-based evidence of CAD were included. The exclusion criteria included bradycardia, unstable angina, recent cardiovascular event, heart block, and hypotension.
There was a 10-day placebo pre-phase during which the participants underwent 48-hour ambulatory monitoring for confirmation of two or more episodes of transient myocardial ischemia. During the treatment phase, the patients in each study arm received 10 mg of bisoprolol once daily or 20 mg of nifedipine twice daily for 4 weeks, followed by double of that dose for another 4 weeks. 48-hour Holter recordings were repeated after 4 and 8 weeks. In addition, data on anginal attacks during the preceding week were also recorded at 4 and 8 weeks. Apart from study medications no patient received any of the following drugs with potential to affect the study results: long-acting nitrates, other beta-blockers, other calcium channel-blockers, angiotensin converting enzyme inhibitors, alpha-blockers, beta-2-agonists, tricyclic antidepressants, antiarrhythmic agents, and digitalis.
Summary of Key Results
A total of 330 patients were randomized of which 161 patients received bisoprolol and 169 received nifedipine. There were no significant between the two groups at baseline. The data for dropouts, patients with ineligible tapes, and those with protocol violations were excluded. Thus, after 4 weeks (low-dose phase), data for 133 and 135 patients in the bisoprolol and nifedipine groups, respectively were analyzed; while the data of 111 and 112 patients, respectively were analyzed after 8 weeks (double-dose phase).
Regarding the efficacy of study medications after the low-dose phase, both study medications showed a clinically and statistically significant reduction in terms of the number of ischemic episodes (mean change with bisoprolol: −4.5; mean change with nifedipine: −2.0), the duration of the ischemic episodes (mean change with bisoprolol: −67.4 minutes; mean change with nifedipine: −28.4 minutes), and the total ischemic burden (mean change with bisoprolol: −134.8; mean change with nifedipine: −77.8) (Figure 1). Moreover, it was shown that all reductions were significantly greater with bisoprolol than with nifedipine (p < 0.0001 for all bisoprolol-nifedipine comparisons). Likewise, a significant heart rate reduction was observed in the bisoprolol group (−13.7 vs. +1.4; p< 0.0001). The efficacy analysis after the double-dose phase showed only marginal incremental reductions, which were significant only for bisoprolol but not for nifedipine.
Figure 1. Bisoprolol Showed Significantly Higher Reductions in Ischemia Than Did Nifedipine.1
Regarding the effects of study medications on the anginal attacks, at 4 weeks, the reduction in the number of weekly anginal events was significant in the bisoprolol group but not in the nifedipine group (mean change with bisoprolol: −2.6 (95% confidence limits: −1.5 to −3.7); mean change with nifedipine: −1.2 (95% confidence limits: 0.1 to −2.5)). However, both groups showed significant weekly anginal events reduction after 8 weeks (mean change with bisoprolol: −3.0; mean change with nifedipine: −2.3).
More importantly, the analysis on the effects of study medications on the circadian variation of ischemia revealed a marked and significant reduction in the morning peak of ischemia in the bisoprolol group. (Figure 2). Interestingly, though the nifedipine group showed overall reduction in ischemia but the circadian pattern of ischemia was unchanged in the nifedipine group.
Figure 2. Significant Reduction in Morning Peak Ischemia with Bisoprolol.1
Discussion and Conclusion
The authors emphasized that though both drugs showed significant efficacy but the results with bisoprolol were more marked in this study, especially the reduction in the morning peak. The authors attributed these differences to a major role of increased demand and elevated resting heart rates in the onset of ambulatory silent ischemia, which was clearly reduced by bisoprolol in this study. The authors suggested that use of bisoprolol along with optimization of medical therapy may reduce the risk of cardiovascular events, especially, those occurring in early morning. The authors concluded that bisoprolol is an effective antianginal and anti-ischemic treatment and may be superior to nifedipine in reduction of silent ischemia.
Reference
- von Arnim T. Medical treatment to reduce total ischemic burden: total ischemic burden bisoprolol study (TIBBS), a multicenter trial comparing bisoprolol and nifedipine. The TIBBS Investigators. J Am Coll Cardiol. 1995;25(1):231-238.
Code
IN-CONCO-00075
