Effect of magnesium sulphate in patients with unstable angina: A double blind, randomized, placebo-controlled study

AIM: Administration of intravenous magnesium sulphate has been shownto be protective during acute myocardial ischaemia and it maytherefore have beneficial effects in unstable angina. The purposeof this study was to assess the effects of a 24-h infusion ofmagnesium in patients with unstable angina. METHODS AND RESULTS: Patients who presented with unstable angina with electrocardiographicchanges were randomized to receive a 24-h intravenous infusionof magnesium or placebo within 12 h of admission. The primaryendpoint was myocardial ischaemia, as assessed by 48 h Holtermonitoring. Resting 12-lead ECGs, creatine kinase-MB releaseand urinary catecholamines were also assessed. Patients werefollowed for 1 month. Thirty-one patients received magnesiumsulphate and 31 placebo. Baseline characteristics and extentof coronary disease were similar in both groups. On 48 h Holtermonitoring, 14 patients (50%) had transient ST segment shiftsin the magnesium group vs 12 patients (46%) in the placebo group.However, there were fewer ischaemic episodes in the magnesiumgroup (51 vs 101, P<0·001) and there was a trend towardsan increase in the total duration of ischaemia in the placebogroup compared to the magnesium group in the second 24 h (2176min vs 719 min respectively, P=0·08). Regression of Twave changes on the 24 h ECG occurred more frequently in patientswho received magnesium compared to those treated with placebo(11 patients vs 0 patients respectively, P<0·005).Creatine kinase-MB release was significantly less at 6 and 24h in patients who received magnesium compared to those treatedwith placebo. Catecholamine excretion was lower in patientstreated with magnesium than in those treated with placebo (adrenaline:1·05±0·16 vs 1·61±0·32ng . mmol^–1 creatinine; noradrenaline: 9·99±1·82vs 18·48±2·41 ng.mmol^–1 creatininerespectively in the first 12 h sample, P<0·05). CONCLUSION: Intravenous magnesium reduces ischaemic ECG changes, creatinekinase-MB release and urinary catecholamine excretion in theacute phase of unstable angina. Thus, magnesium may be a beneficialadditional therapy for these patients. Further studies are requiredto confirm these findings.     

Once- versus twice-daily administration of controlled-release isosorbide-5-mononitrate 60 mg in the treatment of stable angina pectoris: A randomized, double-blind, cross-over study

Thirty-seven patients with chronic, stable angina pectoris wereincluded in a randomized, double-blind cross-over study to assessthe efficacy of once- and twice-daily dosage regimens of 60mg isosorbide-5-mononitrate, in a controlied release formulation(5-ISMN Durules^® Astra). After 2 weeks of treatment, duringa symptom-limited bicycle ergometer exercise test performed3 h after the dose, the time to 1 mm ST segment depression wasobserved to be longer by once-daily than by a twice-daily dosageregimen (614 ± 165 vs 561 ± 148 s, P<0·01).The time to the end of exercise was also significantly prolongedby once-daily dosage, as compared with placebo (693 ±158 and 645 ± 173 s, respectively; P<0·05),which was not observed with the twice-daily regimen. Both dosageregimens still had a significant effect on the prolongationof the time to onset of angina 9 h after the dose: 420 ±164 s by placebo, 492 ± 161 s by once-daily dosage; P<0·01and 466 ± 154 s by twice-daily dosage; P<0·05.Anginal attack rate and nitroglycerin consumption was significantlylower during the once-daily dosage period as compared with placebo;this difference was not evident during the twice-daily administrationof the drug. Controlled-release 5-ISMN 60 mg given once daily was effectivein angina pectoris patients for at least 9 h after the doseand showed no clinical signs of tolerance after 2 weeks of thetreatment. Attenuation of the clinical effect was observed withthe twice-daily (in 12 h intervals) dosage regimen, presumablycaused by constantly high 5-ISMN plasma concentration.     

The effect of meals of differing composition on exercise tolerance in patients with angina pectoris

In this study we compared different dietary constituents andtheir effect on the angina threshold. We compared carbohydrate-rich,fat-rich and balanced liquid diets on effort tolerance in 14patients of mean (range) 61 (41–73) years of age withchronic stable angina. On four different occasions at least1 week apart, patients had exercise treadmill tests after anovernight fast and then after a rest period of I h ingestedone of three different approximately isocalorific (about 4000kJ) liquid drinks of 600 ml consisting mainly of: fat, carbohydrateor a balanced meal with an equal volume of water as control.Meals were given in random order. Analysis of the mean (SD) differences in heart rate betweenfasting and the post-prandial state for the different mealsrevealed a significant increase between water and the othermeals, fat (+4(6) beats.min^–1 P<0·002), balanced(+9(17) beats. min^–1 P<0·004), and carbohydrate(+ 10(12) beats . min ^–1 P<0·002) There wasno significant difference between the groups as regards systolicor diastolic blood pressure. Cardiac output increased followingthe meals but decreased after water; however, there was a significantdifference between water and balanced meals. Exercise tolerancefell following all the meals but was significantly greater aftera balanced (mean (SD) – 108(129) s P<0·001)and carbohydrate meal (– 92(52) s P<0·001).The reduction in exercise duration following a fat meal (–36(53) s) was not significantly different from that followingwater (– 8(43) s) but was significantly smaller than aftera carbohydrate meal (P<0·02). Time to I mm of ST depressionshowed similar changes to that of total exercise duration, beingsignificantly lower after a carbohydrate (mean (SD) –76(77) s P<0·01) and balanced meal (– 76(63)s P<0·0005). Time to 1 mm ST depression, althoughreduced by a fat meal (– 15(84) s) was significantly lessthan after a carbohydrate meal (P<0·02). In conclusion, patients with chronic stable angina have impairedeffort tolerance and a lower angina threshold after high caloriecontaining liquid meals. Meals rich in carbohydrate have greatereffects than meals where the majority of calories are derivedfrom fat. Patients should be advised to avoid exercise in thefirst 30 mm after eating. (Eur Heart J 1996; 17: 394–398)     

Treatment of stable angina pectoris with verapamil hydrochloride: a double blind cross-over study

Verapamil hydrochloride, a calcium antagonist, has been recommendedfor the treatment of angina pectoris. The effectiveness of 3x 120 mg verapamil was tested in 33 male patients with stableangina pectoris. The drug reduced the incidence of anginal episodesfrom 15 (1–98) to two (0–85) in four weeks (median,range); P < 0.01. The nitroglycerin consumption was similarlyreduced. Exercise tolerance on a bicycle ergometer improvedon the average by 10 W(P < 0.05). No side effects were observed. It is concluded that verapamil is an effective drug in the treatmentof stable angina pectoris.     

Antithrombin III supplementation for patients undergoing PTCA for unstable angina pectoris: A controlled randomized double-blind pilot study

BACKGROUND: Thrombin activation may be a higher risk for complications andrestenosis after percutaneous transluminal coronary angioplastyin unstable patients than in patients with stable angina pectoris.The effects of heparin may be partly counteracted by a decreasein antithrombin (III). The primary objectives of this studywere to evaluate whether a subnormal antithrombin level wasassociated with a hypercoagulable state and to evaluate theeffects of antithrombin supplementation, before and after percutaneoustransluminal coronary angioplasty, on biochemical signs of coagulationactivation. Secondary objectives were to evaluate acute complicationsand restenosis rate at 3 months. METHODS: In a double-blind pilot study, 50 patients with unstable angina,with ongoing heparin infusion and with subnormal antithrombinlevels (<85%) were randomized to receive antithrombin supplementationor placebo. Treatment targeted to an antithrombin level of 120%was started with a 2 h intravenous infusion before the percutaneoustransluminal coronary angioplasty and was repeated, if therewere further subnormal values, every 12th hour for 48 h. RESULTS: Angiographic success was 20/25 in the antithrombin group and21/25 in the placebo group (ns). Abrupt closure occurred intwo and one patients in the two groups, respectively. Activationof coagulation measured as elevations of prothrombin fragment1+2, thrombinantithrombin complexes and fibrin D-dimer was seen2 days after the procedure. Baseline levels of fibrin D-dimerwere 68 ± 69 µg. 1^–1 in the antithrombingroup vs 71 ± 46 µg. 1^–1 in the placebo group(ns). Two days after percutaneous transluminal coronary angioplastythe levels increased to 135 ±103 vs 242 ± 150µg. 1^–1, respectively (P<0·05 betweenthe groups). Restenosis at 3 months occurred in 4/20 antithrombinpatients and in 8/21 placebo patients (ns). CONCLUSION: In unstable angina patients with heparin treatment and subnormalantithrombin levels, antithrombin supplementation resulted inless activation of coagulation and a tendency towards less restenosis.     

Enhanced red cell sodium-hydrogen exchange in microvascular angina

OBJECTIVES: Enhanced calcium content in arterial smooth muscle cells andaltered reactivity of coronary vessels to alkalinization havebeen reported in angina pectoris due to impaired motility ofcoronary arteries. An altered function of sodium-hydrogen exchange,a ubiquitous membrane transport system that links proton effluxto calcium drifts, may mediate these phenomena. DESIGN AND SUBJECTS: Twenty patients with microvascular angina (stable effort angina,reversible perfusion defects during effort thallium 201 heartscintigraphy, and angio-graphically normal coronary arteries)were compared to 20 patients with stable effort angina due tocoronary atherosclerosis and 20 healthy subjects. The sodium-hydrogenexchange was defined as the initial fraction of the amiloride-sensitiveproton efflux from red cells with inhibited anion exchanger(pHi 6·00–6·05) into an Na⁺-containing medium(pHo 8·00–8·05). 12-0-tetradecanoylphorbol-13-acetate(TPA, 600 nmol. 1^–1) and staurosporine (100 nmol. 1^–1)were used as phosphorylation modulators in vitro. RESULTS: The mean red blood cell Na⁺/H⁺ exchange was increased in patientswith microvascular angina (451±37 vs 142±17 and124±21 µmol H⁺. 1 cells^–1. min^–1, P<0·01).TPA and staurosporine abolished differences between the groups. CONCLUSION: Microvascular angina is associated with enhanced Na⁺/H⁺ exchangein erythrocytes, probably due to more extensive phosphorylationof the membrane antiporter sites.     

Thoracic epidural anaesthesia in patients with unstable angina pectoris

The effect of high thoracic epidural anaesthesia with intermittentepidural bolus injections of bupivacaine (2.5 or 5 mg ml^-1)was studied in 28 patients with unstable angina pectoris. Themajority of the patients had a history of previous acute myocardialinfarction(s) and/or angina pectoris and severe coronary arterydisease. All patients were treated wth nitroglycerin infusionfor gt;24 h and were included in the study if they had chestpain, not caused by acute myocardial infarction, at bed restor recurrent anginal pain at rest < 2 days after infarction.4.4 ± 0.3 ml of bupivacaine induced a blockade of theupper seven sympathetic segments ( Th_1-7) for 98 ± 9min.Heart rate decreased significantly from 70 ± 3 to 64± 3 beats min^-1 while blood pressure was unaffected bythoracic epidural anaesthesia. In 27 patients (96%) the anaesthesiainduced complete analgesia. Nitroglycerin infusion was discontinueddefinitely within 3 h in 26 patients (93%) and pain was thereaftercontrolled by means of thoracic epidural anaesthesia as thesole treatment in 23 patients (82%) and as the major treatmentin 25 patients (89%). Twenty-one patients (75%) were fully mobilizedand stabilized. Treatment with thoracic epidural anaesthesialasted for 6.0 ± 1.1 days. The number of daily epiduralinjections decreased significantly with time from 2.7 ±0.3the first day to 0.9 ± 0.3 the fourth day (P>0.01,n = 19). Two patients developed acute myocardial infarctionduring the anaesthesia treatment period, and one of these patientsdied. Exercise stress testing was performed on eight patients threeto five days after the start of thoracic epidural anaesthesia.At a comparable workload, ST-segment depression was significantly(P>0.05) less pronounced during anaesthesia ( – 0.6± 0.1 mm) compared with control ( – 1.3 ±0.2mm). The respective heart rate values were 95 ± 7and 107 ± 7 beats min ^-1 (P > 0.05), while systolicor diastolic blood pressure did not differ between the two conditions. We conclude that blockade of cardiac sympathetic afferents andefferents by means of thoracic epidural anaesthesia can effectivelytreat pain and stabilize patients with unstable angina pectorisrefractory to medical treatment. Furthermore, thoracic epiduralanaesthesia attenuates stress-induced myocardial ischaemia;thus, it may be an efficient supplementary treatment for thecontrol of pain and for stabilizing patients with unstable anginapectoris during diagnostic procedures and prior to coronarysurgery or angioplasty.     

Long-term outcome of patients with incomplete vs complete revascularization after multivessel PTCA: A report from the NHLBI PTCA Registry

Background Incomplete revascularization is frequently the goalas well as the final outcome in patients with multivessel coronarydisease undergoing PTCA. However, the long-term impact of incompleterevascularization is not known and this common PTCA strategydeserves further scrutiny. Methods and results Complete revascularization was achievedin 132 of 757 patients with multivessel disease in the 1985–86NHLBI PTCA Registry. Compared to patients in whom complete revascularizationwas achieved, patients with incomplete revascularization wereolder (P<0·05), more likely to be females (P<0·05)and to have recent myocardial infarction (P<0·05),unstable angina (P<0·001), and urgent or emergentPTCA (P<0·001). Early death, Q wave myocardial infarctionand CABG rates were higher in patients with incomplete thanin those with complete revascularization [significantly different(P<0·05) only for emergency and elective CABG]. At9 years, nearly twice as many patients with incomplete revascularizationexperienced recurrent angina (19% vs 10% for patients with completerevascularization,P<0·05). Patients with completerevascularization were more likely to undergo repeat PTCA thanthose with incomplete revascularization (40% vs 30%,P<0·05).Patients with incomplete revascularization were more likelyto undergo CABG than patients with complete revascularization(32% vs 14%,P<0·001; adjusted risk 2·56, 95%CI 1·60, 4·10). Among patients with incompleterevascularization, those in whom PTCA was intended but not attemptedhad the highest early event rates and late CABG rates. Finally,the adjusted risk of dying, having a Q wave myocardial infarction,recurrent angina or repeat PTCA was not different at 9-yearfollow-up among patients with and without complete revascularization. Conclusions Complete revascularization achieved by PTCA reduceslate occurrence of CABG, but not adjusted rates of death, Qwave myocardial infarction, recurrent angina, and repeat PTCAin patients with multivessel coronary disease. These data tendto support the PTCA strategy of incomplete revascularizationin patients with multivessel disease when complete revascularizationis not feasible or not planned before the procedure.     

Pharmacokinetics and additional anti-ischaemic effectiveness of amlodipine, a once-daily calcium antagonist, during acute and long-term therapy of stable angina pectoris in patients pre-treated with a beta-blocker

Amlodipine 10 mg was evaluated/or additional anti-ischaemicand anti-anginal efficacy in 14 patients pre-treated with aßblocker who had documented coronary artery disease,stable angina pectoris, and 2 mm of exercise-induced ST segmentdepression. For 2 days the patients received open-label amlodipineand then, according to a randomized, placebo controlled, cross-overand double-blind protocol, they were treated with amlodipineor placebo, respectively, once a day for 3 weeks each. Exercisetests and blood sampling for plasma concentrations of amlodipinewere performed at 8 and at 24 h after dosing on both days ofacute testing as well as on day 18 of chronic treatment. During chronic treatment, when plasma concentrations fluctuatedbetween 23.5 ng. ml^–1 at 8 h and 14 ng.ml^–1 at 24h post-dosing, ST segment depression at an individually comparableworkload was significantly decreased by 28% compared with placebo(P < 0.005) at both points in time. Increases in ischaemia-freeworkload capacity amounted to 76% (P < 0.005) and to 81%(P < 0.01) at 8 and at 24 h, respectively. The number ofanginal attacks was reduced by 39% (P < 0.05). Conversely,after initial dosing, i.e. when plasma concentrations declinedfrom 4.7 ng.ml^–1 to 3.9ng.ml^–1, influences uponischaemic parameters compared to control values were markedlyless at 24 h as opposed to 8 h. There were no untoward sideeffects observed at any point in time. Thus, a combination of amlodipine 10 mg with a ß-blockerenables additional anti-ischaemic and anti-anginal therapeuticcoverage for 24 h during long-term treatment, facilitating patientcompliance through once-daily administration.     

Effects of mental and physical stress on platelet function in patients with stable angina pectoris and healthy controls

The effects of mental and physical stress on platelet functionin patients with stable angina pectoris and healthy controlswere investigated. Platelet function was studied at rest, andduring mental stress (colour word test), or after exercise (bicycleergometry), in 113 angina patients (21 on aspirin) and 50 matchedcontrols. Platelet function was assessed by filtragometry exvivo (reflecting platelet aggregability), by measuring plateletsecretion (ß thromboglobulin and platelet factor 4levels in plasma), and by Born aggregometry in vitro. At rest, platelet function did not differ between patients andcontrols. Exercise increased platelet aggregability and secretionsimilarly in both groups. Aspirin did not attenuate the plateletactivating effect of exercise despite inhibition at rest. Mentalstress increased heart rate, blood pressure and plasma catecholamines,but platelet responses were highly variable. However, mentalstress tended to shorten filtragometry readings in patientsbut not in controls (P<0·05 between the groups); plasmaß-thromboglobulin showed a similar difference betweenpatients and controls (P<0·05 between the groups;aspirin-treated patients included). Physical exercise activates platelets in patients with stableangina pectoris and healthy controls. Aspirin is not an effectiveinhibitor of exercise-induced platelet aggregation. Plateletresponses to mental stress are variable, but more pronouncedin angina patients.     

Both endothelium-dependent and endothelium-independent function is impaired in patients with angina pectoris and normal coronary angiograms

Background The aim of this study was to investigate both endothelium-dependentand endothelium-independent vasodilatation in syndrome X patients.Recently selective impairment of endothelium-dependent functionhas been reported in a small number of syndrome X patients.However, other investigators have reported impaired endothelium-independentfunction. Methods We infused the endothelium-independent vasodilatorspapaverine and glyceryl trinitrate, and endothelium-dependentvasodilator acetyicholine in the left coronary artery of 35patients with syndrome X and in 17 control subjects (atypicalchest pain, negative exercise test, and normal coronary angiograms).Coronary blood flow was measured with an intracoronary Dopplercatheter positioned in the proximal left anterior descendingcoronary artery, and the artery diameter was assessed usingquantitative coronary angiography. Result The mean increase in coronary blood flow in responseto a 12 mg dose of papaverine was significantly less in thesyndrome X group (185±74% vs 411 ± 59%, P0·001).The increase in coronary blood flow in response to acetylcholine,at doses of 1, 3, 10, and 30 µg. min^–1, was alsosignificantly lower in the syndrome X group (12±13 (P>0·05),41 ± 33, 57 ± 68, and 124 ± 87% (P>0·001))as compared to the control group (76 ± 49, 214 ±116, 355 ± 115, and 361 ± 74%). Conclusion These findings demonstrate that both endothelium-dependentand endothelium-independent dilatation of the coronary microvasculatureis impaired in syndrome X.     

Effect of 48-h intravenous trimetazidine on short- and long-term outcomes of patients with acute myocardial infarction, with and without thrombolytic therapy. A double-blind, placebo-controlled, randomized trial

Aims To compare the effect of trimetazidine (TMZ) versus placeboadministered during the acute phase of myocardial infarctionon long- and short-term mortality. Methods and Results EMIP–FR (European Myocardial InfarctionProject–Free Radicals) was a prospective, double-blind,European multicentre trial in which 19725 patients, presentingsymptoms of acute myocardial infarction within the previous24h were randomized. Stratification was according to thrombolytictherapy (56%) or not (44%). An intravenous bolus injection oftrimetazidine (40mg) was given just before or simultaneouslywith thrombolysis, followed by continuous infusion (60mg.24h^–1)for 48h. Overall, no difference was found between trimetazidineand placebo for the main end-point, short-term (35-day) mortality,(P=0·98) in an intention-to-treat analysis. This wasthe result of opposing trends in the two strata. Thrombolysedpatients showed a tendency towards more short-term deaths withtrimetazidine, compared to placebo (trimetazidine: 11·3%,placebo: 10·5%, P=0·15) and non-thrombolysed patientsthe converse (trimetazidine: 14·0%, placebo: 15·1%,P=0·14). In a per-protocol analysis the beneficial effectof trimetazidine for non-thrombolysed patients became statisticallysignificant (trimetazidine: 13·3%, placebo: 15·1%,P=0·027). Conclusion Trimetazidine does not reduce mortality in patientsundergoing thrombolytic therapy; however, it might have somebeneficial effect for non-thrombolysed patients.     

A prospective study of the role of lipoprotein(a) in the pathogenesis of unstable angina

AIM: Lipoprotein(a) is considered to be a risk factor for atherothromboticdiseases. The aim of the study was to examine the potentialrole of lipoprotein(a) concentrations in patients admitted withunstable angina with particular reference to their cardiac TroponinT concentrations, which identifies a subgroup at high risk ofsubsequent cardiac events. METHODS AND RESULTS: Consecutive patients admitted with chest pain to a single coronarycare unit were studied. One hundred and sixty-seven patientshad a final diagnosis of unstable angina, of whom 56 were cardiacTroponin T-positive. Admission lipoprotein(a) concentrationswere significantly higher in the cardiac Troponin T-positiveunstable angina group as compared to the cardiac Troponin T-negativeunstable angina group: median and interquartile ranges 22·25mg dl^–1 (6·25, 32·0) vs 6·0 mg. dl^–1(2·22, 14·8) respectively) P=0·0004. Ahighly significant correlation was also found between the levelof cardiac Troponin T at diagnosis and the lipoprotein(a) concentration:r_s=0·2798, P=0·0001. CONCLUSION: This study provides the first evidence in man of a significantrole for lipoprotein(a) in unstable angina. The correlationbetween lipoprotein(a) concentration and cardiac Troponin Tconcentration suggests that lipoprotein(a) may be significantlyinvolved in the early failure of plaque rupture stabilization.     

Changes in platelet size and count in unstable angina compared to stable angina or non-cardiac chest pain

Aims An increase in platelet aggregability is associated withunstable angina and myocardial infarction. Platelet size andactivity correlate and mean platelet volume was found to beincreased before acute myocardial infarction. We measured themean platelet volume and platelet count in patients with stableangina, unstable angina and non-cardiac chest pain. Methods and results We studied 981 patients (734 men; 247 women)defined clinically as stable angina (n=688), unstable angina(n=108) and unstable angina requiring immediate angioplasty(n=52). After coronary angiography the patients were subdividedinto single (n=269), double (n=304) and triple-vessel disease(n=311) and the control group of non-cardiac chest pain (n=97).There was no significant difference in platelet count betweenthe control group and patients with 1, 2, or 3-vessel disease.However, the platelet size in patients with coronary arterydisease was significantly larger (single: 8·7±1·19fl;double: 8·7±1·12fl; triple-vessel disease:8·8±1·18fl) than the control group (8·2±0·95fl)(P<0·01). Patients with stable angina similarly hadno significant difference in platelet count compared to thecontrol group but did have a significantly increased mean plateletvolume (8·7±1·13;P<0·01). Incontrast, patients with unstable angina had a decreased plateletcount (245±56x10/l) compared to either stable angina(262±62x10/l;P<0·05) or the control group (261±58x10/l;P<0·05);furthermore, the mean platelet volume (9·4±1·23fl)was significantly greater than for stable angina (P<0·01).Patients with unstable angina requiring immediate PTCA had aneven lower platelet count (231±55x10/l) and higher meanplatelet volume (10·4±1·03fl) (P<0·01)than the rest of the population with unstable angina. Conclusions In stable angina the platelet count is unchangedcompared to patients with normal coronary arteries but the plateletsize is increased. However, in unstable angina there is a decreasein platelet count and an even larger increase in platelet size.We interpret this as meaning that unstable angina might be associatedor preceded by an increase in platelet destruction rate thatis not completely compensated for by an increase in plateletproduction rate. The large, more reactive platelets might becausally related to an ongoing coronary artery obstruction inunstable angina.     

Comparison of two treatment durations (6 days and 14 days) of a low molecular weight heparin with a 6-day treatment of unfractionated heparin in the initial management of unstable angina or non-Q wave myocardial infarction: FRAX.I.S. (FRAxiparine in Ischaemic Syndrome)

Aim To assess the benefit of short-term low molecular weightheparin nadroparin compared with unfractionated heparin in unstableangina or non-Q wave myocardial infraction patients and to determinewhether a longer, 2-week low molecular weight heparin regimenwould offer additional clinical benefit. Patients, Methods and Results This was a multicentre, prospective,randomized, double-blind study in three parallel groups, involving3468 patients. Patients received one of three treatment regimens:the unfractionated heparin group received an intravenous bolusof unfractionated heparin 5000IU, followed by an activated partialthromboplastin time adjusted infusion of unfractionated heparinfor 6±2 days; the nadroparin 6 group received an intravenousbolus of nadroparin 86 anti-Xa IU.kg^–1, followed by twicedaily subcutaneous injections of nadroparin 86 anti-Xa IU.kg^–1for6±2 days, and the nadroparin 14 group received an intravenousbolus of nadroparin 86 anti-Xa IU.kg^–1, followed by twicedaily subcutaneous injections of nadroparin 86 anti-Xa IU.kg^–1for14 days. No statistically significant differences were observedbetween the three treatment regimens with respect to the primaryoutcome (cardiac death, myocardial infarction, refractory angina,or recurrence of unstable angina at day 14). The absolute differencesbetween the groups in the incidence of the primary outcome were:–0·3% (P=0·85) for the nadroparin 6 groupvs the unfractionated heparin group and +1·9% (P=0·24)for the nadroparin 14 group vs the unfractionated heparin group.Furthermore, there were no significant intergroup differencesregarding any of the secondary efficacy outcomes. However, therewas an increased risk of major haemorrhages in the nadroparin14 group compared with unfractionated heparin (3·5% vs1·6%;P=0·0035). Conclusions Treatment with nadroparin for 6±2 days providessimilar efficacy and safety to treatment with unfractionatedheparin, for the same period, in the therapeutic managementof acute unstable angina or non-Q wave myocardial infarction,and may be easier to administer. A prolonged regimen of nadroparin(14 days) does not provide any additional clinical benefit.     

Functional characteristics of myocardial bridging: A combined angiographic and intracoronary Doppler flow study

AIMS: Combined quantitative coronary angiography and intracoronaryDoppler flow velocity measurements were performed to study theunderlying haemodynamic mechanisms leading to myocardial ischaemiain patients with myocardial bridging in the absence of coronaryartery disease. METHODS AND RESULTS: In 42 symptomatic patients with myocardial bridging of the leftanterior descending coronary artery, quantitative coronary angiographywas used to measure absolute and relative vessel diameters duringsystole and diastole. In 14 patients, serial frame-by-framediameter quantification during a complete cardiac cycle wasperformed. Intracoronary blood flow velocities were determinedusing a 0·014 inch Doppler flow guide wire proximal,within, and distal to myocardial bridges, and coronary flowreserve was calculated. Quantitative coronary angiography revealeda maximal systolic lumen diameter reduction of 71 ± 16%with a persistent diameter reduction of 35 ± 13% duringmid-diastole. Flow velocities revealed increased average diastolicpeak flow velocities within myocardial bridges of 38·6± 19 cm. s^–1 vs 22·4 ± 7·7cm. s^–1 proximal and 18·6±4·6cm.s^–1 distal (P<0·001), which increased duringrapid pacing (64·7 ± 25 cm. s^–1, P<0·001vs baseline). Coronary flow reserve distal to myocardial bridgeswas 2·3 ± 0·9 (vs 2·9 ± 0·9proximal, P<0·05). There was a characteristic Dopplerflow profile within myocardial bridges with an early diastolicovershoot, which was further augmented during rapid pacing. CONCLUSION: Myocardial bridging is characterized by a delay in diastoliclumen gain and a concomitant increase in diastolic intracoronaryDoppler flow velocities, which are enhanced by rapid pacing.In combination with a reduced coronary flow reserve and anginalsymptoms these findings support the concept of a haemodynamicallysignificant obstruction to coronary flow due to myocardial bridgingin a selected subset of patients.     

Effects of transdermal nitroglycerin in combination with an ACE inhibitor in patients with chronic stable angina pectoris

We have previously shown that transdermal nitroglycerin mayinduce an increase in the activity of the adrenergic and therenin-angiotensin-aldosterone systems (SRAA) in patients withchronic stable angina pectoris (SA); when the activation ofthese systems is more pronounced, the antianginal effect ofthis drug seems to be reduced. The aim of this study was toevaluate the antianginal efficacy of transdermal nitroglycerinadministration (TTS-NG 10 mg. 24 h^–1) in combination withan ACE inhibitor without sulphydryl groups (BNZ, benazepril10 mg b.i.d.) in respect to placebo, or to TTS-NG or BNZ administeredas monotherapy. Twenty-four patients (21M, 3F) were admittedto this multicentre, randomized, double-blind, latin square,placebo-controlled study. Patients received all the treatments(placebo, TTS-NG, BNZ and BNZ+ TTS-NG) each for one week; atthe end of each week patients performed two exercise testi 2and 22 h post-dosing. Two hours post-dosing, exercise durationat 1 mm ST depression was significantly increased in respectto placebo during TTS-NG (P<0.05) and TTS-NG+BNZ (P<0.05)treatments. Two hours post-dosing, exercise duration at peakexercise was also increased in respect to placebo during TTS-NG(P<0.05) ana TTS-NG+BNZ (P<0.05); 22 h post-dosing theincrease in exercise duration was significant only during TTS-NG+BNZtreatment (P<0.05) in respect to placebo, but not duringTTS-NG given alone. Rate-pressure product at 1 mm ST depressionwas significantly increased 2 h post-dosing during TTS-NG treatment(P<005). In conclusion, these results suggest that ACE inhibitor administrationgiven in combination with TTS-NG can induce a statisticallysignificant increase in exercise duration in stable angina patientsin respect of placebo, 22 h post-dosing. The clinical significanceof this finding must be evaluated in further studies.     

Prognostic significance of angina pectoris recurring soon after myocardial infarction

The prognostic significance of an early occurrence, or recurrence,of angina pectoris after myocardial infarction was studied in254 patients (221 male, 33 female; mean age 58±11 years).During the in-hospital rehabilitation program, 41 patients (16%)had anginal pain. The mean follow-up was 21 months (range 12–33months). Among the 254 patients, 21 died, five had recurrentmyocardial infarction, 13 had unstable angina, and 22 underwentaortocoronary bypass surgery. An early recurrence of anginapectoris was predictive of combined (medical+surgical) events(21 patients, P<0.05), medical events (11 patients, P<0.05)and surgical events (10 patients, P<0.001), but failed topredict individual death (six patients), recurrent myocardialinfarction (two patients) or unstable angina (three patients).Of the events that occurred in the 254 patients, 34% were predictedby the early recurrence of angina pectoris. Early post-infarctionangina was observed more frequently in older patients and patientswith previous history of angina pectoris. This represents animportant prognostic factor after myocardial infarction, whichdefines a high-risk group of patients requiring further investigationand appropriate therapeutic approaches.     

Occurrence of angina pectoris prior to acute myocardial infarction and its relation to prognosis

In 917 patients with acute myocardial infarction (AMI) we evaluatedthe impact of previous angina pectoris on the prognosis. Thirty-fourpercent of the patients had chronic angina prior to AMI, and22% had angina pectoris of short duration. Patients with chronicangina pectoris differed from the remaining patients havinga more frequent previous history of AMI, diabetes mellitus,hypertension, and congestive heart failure. They less frequentlydeveloped a Q-wave AMI, and had smaller infarcts according tomaximum serum-enzyme activity as compared with the remainingpatients. They had a higher one-year mortality rate (36%) ascompared with those having angina pectoris of short duration(22%), and those with no angina pectoris (26%). Their reinfarctionrate was also higher (26%) as compared with that in the othertwo groups (15% and 9% respectively). In a multivariate analysisconsidering age, sex, clinical history, initial symptoms, initialelectrocardiogram and estimated infarct size, previous chronicangina pectoris was not an independent risk factor for death,but was independently associated with the risk of reinfarction(P<0.001) Among patients with a history of angina pectoristhe outcome was related to medication prior to onset of AMIand at discharge from hospital. Patients in whom beta-blockerswere prescribed at discharge had a one-year mortality of 13%as compared with 30% in the remaining patients (P<0.001).     

Randomized placebo-controlled study of the effects of simvastatin on haemostatic variables, lipoproteins and free fatty acids

The Oxford Cholesterol Study is a randomized placebo-controlledtrial designed primarily to assess the effects of simvastatinon blood cholesterol levels and side-effects in preparationfor a large, long-term trial of the effects of cholesterol-loweringdrug therapy on mortality. At present there is only limitedevidence from randomized comparisons of the effects of HMG-CoAreductase inhibitors, such as simvastatin, on thrombogenic,as distinct from atherogenic, pathways in coronary heart disease.The present sub-study was carried out to assess the effectsof simvastatin on a range of haemostatic variables, as wellas on free fatty acids and on lipoprotein fractions not studiedin detail previously. At an average of about 2 years after starting study treatment,non-fasting blood samples were obtained from a sequential sampleof 162 participants who had been randomly allocated to receive40 mg (54 patients) or 20 mg (57 patients) daily simvastatinor matching placebo treatment (51 patients). Only patients whoreported taking their study treatment and who were not knownto be diabetic or to be taking some other lipid lowering treatmentwere to be included. The principal comparisons were to be ofthose allocated simvastatin (i.e. 20 and 40 mg doses combined)vs those allocated placebo. Among patients allocated simvastatin, marginally significantlower factor VII antigen levels (12·10%±6·08of standard; 2P<0·05) and non-significantly lowerfactor VII coagulant activity (8·24%±4·99of standard) and fibrinogen concentrations (0·10±0·08g.l^–1) were observed. In contrast, plasminogen activatorinhibitor activity was significantly higher (2·62±1·03IU; 2P<0·01) among patients allocated simvastatin.No significant differences were seen in the other haemostaticfactors studied (e.g. prothrombin fragment 1·2, factorXII and C$$$ inhibitor). Total free fatty acid concentrationwas marginally significantly reduced (2P=0·02) with simvastatin,but none of the reductions in individual free fatty acids wassignificant. Lipoprotein fractions were only measured amongpatients allocated 40 mg daily simvastatin or placebo. Comparedwith placebo, simvastatin produced significant decreases notonly in LDL cholesterol (1·74±0·15 mmol.1^–1;2P<0·0001) but also in VLDL cholesterol (0·28±0·08mmol.1^–1; 2P<0·001) and IDL cholesterol (0·17±0·03mmol.1^–1; 2P<0·0001). There were also lowertriglyceride levels associated with LDL (0·07±0·01mmol.1^–1; 2P<0·0001), IDL (0·03±0·01mmol.1^–1; 2P<0·01) and VLDL (0·27±0·14;2P=0·05). The effects of simvastatin on haemostatic variables appear tobe far less marked than its lipid effects. Given the associationsof haemostatic factors with coronary heart disease incidence,larger randomized comparisons of the HMG-CoA re1ductase inhibitors(and of the newer fibrates, which may produce greater effects)are needed to provide more reliable estimates of the extentto which they influence these variables.