Heart rate variability and ischaemia in patients with coronary heart disease and stable angina pectoris; influence of drug therapy and prognostic value. TIBBS Investigators Group. Total Ischemic Burden Bisoprolol Study.

AIMS: Determination of the influence of therapy with bisoprolol and nifedipine on the heart rate variability of patients from the Total Ischemic Burden Bisoprolol Study and examination of the prognostic value. METHODS AND RESULTS: Four hundred and twenty-two patients with stable angina were included. The heart rate variability was determined over a period of 24 h. Parameters determined: standard deviation of the mean of all corrected RR intervals, standard deviation of all 5 min mean cycle lengths, square root of the mean of the squared differences of successive corrected RR intervals. Nifedipine reduced the mean values of all heart rate variability parameters tested. Square root of the mean of the square differences of successive corrected RR intervals increased under bisoprolol. Standard deviation of the mean of all corrected RR intervals and standard deviation of all 5 min mean cycle lengths increased from low baseline values and declined from higher baseline values. The increase in heart rate variability under therapy was accompanied by a tendency towards a better prognosis. Patients with an increase in heart rate variability and simultaneous complete suppression of ischaemia under therapy displayed no serious events in the course of one year. CONCLUSIONS: The increase in the heart rate variability, which can be regarded as prognostically favourable, was predominantly observed under bisoprolol. The parameter constellation of an increase in heart rate variability and complete ischaemia suppression on the 48-h Holter ECG was associated with the greatest benefit.

Prognostic significance of transient ischemic episodes: response to treatment shows improved prognosis. Results of the Total Ischemic Burden Bisoprolol Study (TIBBs) follow-up.

OBJECTIVES: The Total Ischemic Burden Bisoprolol Study (TIBBS) follow-up examined cardiac event rates in relation to transient ischemia and its treatment. BACKGROUND: It is unclear whether transient ischemia on the ambulatory electrocardiogram has prognostic implications in stable angina and whether medical treatment can improve the prognosis. METHODS: The TIBBS trial was an 8-week, randomized, controlled comparison of the effects of bisoprolol and nifedipine on transient ischemic episodes in patients with stable angina pectoris. Of the 545 patients screened, 520 (95.4%) could be followed up. Rates of cardiac and noncardiac death, nonfatal acute myocardial infarction, hospital admission for unstable angina and need for coronary artery bypass graft surgery or percutaneous transluminal coronary angioplasty were recorded. RESULTS: A total of 145 events occurred in 120 (23.1%) of 520 patients. Patients with more than six episodes had an event rate of 32.5% compared with 25.0% for patients with two to six episodes and 13.2% for patients with less than two episodes (p < 0.001). Hard events (death, acute myocardial infarction, hospital admission for unstable angina pectoris) were more frequent in patients with two or more ischemic episodes (12.2% vs. 4.7%, p = 0.0049). Patients with a 100% response rate of transient ischemic episodes during the TIBBS trial had a 17.5% event rate at 1 year compared with 32.3% for non-100% responders (p = 0.008). Patients receiving bisoprolol during the TIBBS tria had a lower event rate (22.1%) at 1 year than patients randomized to nifedipine (33.1%, p = 0.033). CONCLUSIONS: In patients with stable angina pectoris, frequent episodes of transient ischemia are a marker for an increased event rate. A 100% response to medical treatment reduces the event rate. The greater reduction of ischemia with bisoprolol than nifedipine during the TIBBS trial translated into an improved outcome at 1 year.

Medical treatment to reduce total ischemic burden: total ischemic burden bisoprolol study (TIBBS), a multicenter trial comparing bisoprolol and nifedipine. The TIBBS Investigators.

OBJECTIVES: We compared the effects of bisoprolol on transient myocardial ischemia with those of nifedipine in patients with chronic stable angina. BACKGROUND: Both beta-adrenergic blocking agents and calcium antagonists reduce transient ischemic episodes, but comparisons of these agents have been made in only a few larger studies. METHODS: The Total Ischemic Burden Bisoprolol Study (TIBBS) was a randomized double-blind controlled study with two parallel groups; 330 patients from 30 centers in seven European countries with stable angina pectoris, a positive exercise test and more than two transient ischemic episodes during 48 h of Holter monitoring (central evaluation) were included. Of these patients 161 were randomized to receive bisoprolol and 169 to receive nifedipine slow release. There were two treatment phases of 4 weeks each, with 48-h Holter monitoring after each phase. During phase 1, patients received either 10 mg of bisoprolol daily or 2 x 20 mg of nifedipine slow release. During phase 2, they received either 20 mg of bisoprolol daily or 2 x 40 mg of nifedipine slow release. RESULTS: In phase 1 of the trial, 4 weeks of bisoprolol therapy (10 mg daily) reduced the mean [+/- SD] number of transient ischemic episodes from 8.1 +/- 0.6 to 3.2 +/- 0.4/48 h. Nifedipine (2 x 20 mg) reduced transient ischemic episodes from 8.3 +/- 0.5 to 5.9 +/- 0.4/48 h. Total duration of ischemia was reduced from 99.3 +/- 10.1 to 31.9 +/- 5.5 min/48 h with bisoprolol and from 101 +/- 9.1 to 72.6 +/- 8.1 min/48 h with nifedipine. Reductions were statistically significant for both drugs; the difference between bisoprolol and nifedipine was also significant (p < 0.0001). Bisoprolol reduced the heart rate at onset of episodes by 13.7 +/- 1.4 beats/min from a baseline value of 99.5 +/- 1.2 beats/min (p < 0.001). Heart rate was unchanged with nifedipine. Bisoprolol had significantly higher responder rates than nifedipine. Doubling of the dose in phase 2 of the trial had small additive effects. Only bisoprolol showed a marked circadian effect by reducing the morning peak of transient ischemic episodes (by 68% at peak time, 8:00 to 8:59 AM). CONCLUSIONS: Both bisoprolol and nifedipine reduced the number and duration of transient ischemic episodes in patients with chronic stable angina. Bisoprolol was significantly more effective than nifedipine in both doses tested and reduced the morning peak of ischemic activity.

Nitrates and calcium antagonists for silent myocardial ischemia.

Continuous Holter monitoring of patients with coronary heart disease can show transient ischemic episodes occurring spontaneously with or without angina throughout the day. A controlled double-blind trial was conducted comparing the effects of isosorbide-5-mononitrate (IS-5-MN) and nifedipine in patients with documented transient ischemic episodes. Seventy-five percent of the ischemic episodes were not accompanied by pain. Twenty patients with documented coronary heart disease were included; 15 finished the 4-week study (1 patient had headaches, 1 thyrotoxicosis, 1 hypertensive crisis and 2 unstable angina). On a dual-channel FM-recorded electrocardiogram, ischemic episodes were counted when ST deviation was greater than 1 mm for greater than 1 minute. Patients received IS-5-MN (20 mg 3 times a day or 50 mg in a sustained-release tablet) or nifedipine (20 mg in a sustained-release tablet 3 times a day) in random order over four 1-week periods. At the end of each week, Holter monitoring was repeated and showed reductions of episodes by 67% and 67% after weeks of IS-5-MN therapy and 56% and 58% after weeks of nifedipine therapy (all p less than 0.05). Painful and painless episodes were reduced to a similar extent. Individual responses showed great variability, and in all treatment periods not more than half of the patients were completely free of ischemic episodes. One of the 12 patients did not respond to either way of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Isosorbide-5-mononitrate and nifedipine can reduce ischaemic ST-segment changes during Holter monitoring in patients with spontaneous angina pectoris.

Ambulatory electrocardiographic monitoring is as yet the only method to document ischaemia occurring in patients with coronary artery disease during their normal daily activities. We conducted a controlled double-blind trial comparing the effects of isosorbide-5-mononitrate (IS-5-MN) 3 X 20 mg, sustained release IS-5-MN 50 mg once daily and sustained release nifedipine 3 X 20 mg in patients with documented coronary heart disease and transient ischaemic episodes. 20 patients were included, 15 finished the four-week study period. Two developed unstable angina, one headache, one thyreotoxicosis, one a hypertensive crisis and were thus withdrawn. On dual-channel FM recorded ECG ischaemic episodes were counted when ST-deviation was more than 1 mm for more than 1 min. 70% of the ischaemic episodes were asymptomatic. Patients received IS-5-MN and nifedipine in 4 weekly periods in random order. At the end of each weekly period, ambulatory monitoring was repeated and showed reduction of episodes by 68% and 68% for IS-5-MN weeks and 56% and 60% for nifedipine weeks all P less than 0.05 vs. pretreatment. The reduction in number and duration of episodes was similar for painful and painless episodes. Individual responses were very variable and in all treatment periods only around half of the patients became completely free of ischaemic episodes. Two of the 15 patients did not respond to either way of treatment. In conclusion--treatment effects for a group of patients with transient--predominantly silent--ischaemia can be documented with ambulatory electrocardiographic monitoring.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of isosorbide 5-mononitrate 20 mg, sustained-release 50 mg and sustained-release nifedipine 20 mg on ischaemic ST-segment changes during Holter monitoring. A double-blind cross-over study in patients with spontaneous angina pectoris.

Objective evidence of transient ischaemia can be obtained by ST-segment analysis of ambulatory ECG recordings. To compare the anti-ischaemic effects of isosorbide 5-mononitrate (IS 5-MN) and nifedipine in sustained-release formulations, we entered 16 patients with documented spontaneous ischaemic episodes in a double-blind cross-over study. The study consisted of four 1-week treatment periods with repeated 24-hour recordings at the end of each period. Nifedipine 3 X 20 mg/day was compared to IS 5-MN 3 X 20 mg/day and IS 5-MN 50 mg once daily for 1 week each. 12 patients completed the study protocol: 1 withdrew because of headache, 1 developed hyperthyroidism and in 2 patients the study was discontinued because the anginal symptoms became unstable. For the entire group both ways of treatment showed beneficial effects with significant reductions of the number of episodes (reduced by 65-68%, p less than 0.01), duration of episodes (reduced by 65-70%, p less than 0.05) and degree of ST deviation (reduced by 39-70%, p less than 0.05). With both IS 5-MN (7 of 12 and 6 of 12 patients) and nifedipine (5 of 12 and 8 of 12) a part of the group of patients became free of ischaemic episodes. In individual patients, however, different patterns of response were observed: 3/12 showed a complete response on both treatments, 1/12 was free on IS 5-MN only and 1/12 on nifedipine only.(ABSTRACT TRUNCATED AT 250 WORDS)

[Intracoronary nifedipine--separation of drug specific and vehicle-induced effects]. / Nifedipin intrakoronar--Trennung wirkstoffspezifischer und lösungsmittelbedingter Effekte.

In 22 patients we studied the effects of 0.2 mg nifedipine given intracoronary during the course of routine PTCA. In 9 patients the effect of the nifedipine-free solvent was additionally tested. Injections were made through the guiding catheters or balloon catheters as pre- and poststenotic injections. We monitored frequency and character of pain, ECG changes (continuous recording of full 12-lead ECG) and pressure recordings from the left ventricle and pre- and poststenotic coronary artery. Short-lasting "stinging" pain sensations were described by 41% of the patients after nifedipine and 33% after solvent injection (n.s.). Patients described the pain as different from their usual angina pectoris. Pain was more frequent after poststenotic injections (through the balloon catheter) than after pre-stenotic injections (59% vs. 19%, p less than 0.01). ECG changes were peaking T waves, ST elevation and ST depression. They were recorded after pre-stenotic injections in 21 of 22 cases for nifedipine and 6 of 9 for solvent and after poststenotic injections in 22 of 22 cases for nifedipine and 8 of 9 cases for solvent. After nifedipine 0.2 mg i.c. the pressures decreased by 3.5% pre-stenotic and 9.7% post-stenotic. LVEDP increased by 10.7%. Our results show that pain sensations and electrocardiographic changes occur with similar character and frequency after i.c. injections of nifedipine or nifedipine-free solvent. Thus these effects do not seem to be caused by nifedipine. Hemodynamic effects were small and there was no disproportionate decrease of poststenotic pressure.