The impact of diabetes or elevated fasting blood glucose on cardiovascular prognosis in patients with stable angina pectoris.

AIMS: To examine the influences of diabetes and elevated fasting blood glucose on cardiovascular prognosis in patients with stable angina pectoris. METHODS: In a prospective study of 809 patients with stable angina pectoris randomized to receive metoprolol or verapamil, a subgroup of 69 diabetic patients was compared with non-diabetic patients with respect to the risk of cardiovascular (CV) death, non-fatal myocardial infarction (MI) and revascularization. We also analysed a subgroup of 67 patients with fasting blood glucose > or = 6.1 mmol/l, defined according to the most recent revised guidelines for the diagnosis of diabetes mellitus. Fasting blood glucose was measured in venous whole blood at baseline. RESULTS: The diabetic patients had a greater risk-factor burden, with a higher prevalence of hypertension, more likely to be male, a tendency towards a higher prevalence of previous MI, and higher triglyceride and lower high-density lipoprotein (HDL)-cholesterol levels. In multivariate analyses, diabetes was an independent risk factor for CV events with a relative risk of 2.64 (CI 1.39-5.00; P < 0.001) for CV death/MI, and 1.79 (CI 1.02-3.15; P < 0.01) for revascularization. Blood glucose > or = 6.1 mmol/l without a diagnosis of diabetes mellitus was found in 67 patients, and predicted CV death/MI [relative risk 2.76 (CI 1.97-3.84)] in both univariate and multivariate analyses. The prognosis of diabetic or hyperglycaemic patients did not differ significantly with metoprolol compared with verapamil treatment. CONCLUSIONS: Diabetes mellitus is an independent risk factor for CV death/MI and for revascularization in patients with stable angina pectoris. Elevated fasting blood glucose was seen in 9% of patients without known diabetes and was an equally strong and independent risk factor for CV death/MI as diagnosed and treated diabetes.

Prognostic implications of autonomic function assessed by analyses of catecholamines and heart rate variability in stable angina pectoris.

OBJECTIVE: To assess the prognostic impact of autonomic activity, as reflected by catecholamines and heart rate variability (HRV), in patients with stable angina pectoris. DESIGN: Double blind, randomised treatment with metoprolol or verapamil. 24 hour ambulatory ECG, used for frequency domain analyses of HRV, and symptom limited exercise tests at baseline and after one month of treatment. Catecholamine concentrations were measured in plasma (rest and exercise) and urine. SETTING: Single centre at a university hospital. PATIENTS: 641 patients (449 men) with stable angina pectoris. MAIN OUTCOME MEASURES: Cardiovascular (CV) death, non-fatal myocardial infarction (MI). RESULTS: During follow up (median 40 months) there were 27 CV deaths and 26 MIs. Patients who died of CV causes had lower total power and high (HF), low (LF), and very low (VLF) frequency components of HRV. HRV was not altered in patients who suffered non-fatal MI. Catecholamines did not differ between patients with and those without events. Metoprolol increased HRV. Verapamil decreased noradrenaline (norepinephrine) excretion. Multivariate Cox analyses showed that total power, HF, LF, and VLF independently predicted CV death (also non-sudden death) but not MI. LF:HF ratios and catecholamines were not related to prognosis. Treatment effects on HRV did not influence prognosis. CONCLUSIONS: Low HRV predicted CV death but not non-fatal MI. Neither the LF:HF ratio nor catecholamines carried any prognostic information. Metoprolol and verapamil influenced LF, HF, and catecholamines differently but treatment effects were not related to prognosis.

Evaluation of various electrocardiographic criteria for left ventricular hypertrophy in patients with stable angina pectoris: influence of using modified limb electrodes.

BACKGROUND: Left ventricular hypertrophy (LVH) in coronary heart disease is associated with poor prognosis. Electrocardiography (ECG) criteria for LVH, when using ECG with modified limb electrode positions, has not been validated in patients with angina pectoris. METHODS: Echocardiography and resting ECGs with modified limb electrode positions, i.e. with the limb leads placed on the abdomen instead of the extremities, were registered from 468 patients (295 men) with stable angina pectoris. To evaluate the influence of using modified limb electrode positions, ECGs with standard and modified limb electrode positions were compared in a control group consisting of 50 other patients. RESULTS: The ECG criteria for LVH according to the Perugia score, the Minnesota code and Romhilt & Estes reached the highest sensitivity values, 27-31% in men and 24-38% in women, while the sensitivities of different Cornell criteria were as low as 6-10% in men and 19-29% in women. In the control group, the R- and S-wave amplitudes of the precordial leads were only slightly changed, as expected, whereas those of the limb leads changed considerably. Based on these results, we corrected aVL in the main study, which increased the sensitivity of the Cornell voltage criteria from 15 to 30%, while the specificity was maintained at 95%. CONCLUSIONS: ECGs registered with modified limb electrode positions can be used to detect LVH with traditional ECG criteria, but changes in the limb leads are considerable and influence the sensitivities.

Prognostic implications of intima-media thickness and plaques in the carotid and femoral arteries in patients with stable angina pectoris.

BACKGROUND: Ultrasonographic assessments of intima-media thickness and plaques in the carotid artery are widely used as surrogate markers for coronary atherosclerosis, but prospective evaluations are scarce and appear to be lacking in patients with coronary artery disease. Ultrasonographic evaluations of femoral vascular changes have not been studied prospectively. METHODS AND RESULTS: In the Angina Prognosis Study in Stockholm (APSIS), 809 patients with stable angina pectoris were studied prospectively during double-blind treatment with verapamil or metoprolol. Ultrasonographic assessments of intima-media thickness, lumen diameter and plaques in the carotid and femoral arteries were evaluated in a subgroup of 558 patients (182 females) with a mean age of 60 +/-7 years, and related to the risk of cardiovascular death (n = 18) or non-fatal myocardial infarction (n = 26), or revascularization (n = 70) during follow-up (median 3.0 years). Univariate Cox regression analyses showed that carotid intima-media thickness and plaques were related to the risk of cardiovascular death or myocardial infarction. Femoral intima-media thickness was related to cardiovascular death or myocardial infarction, as well as to revascularization, whereas femoral plaques were only related to the latter. After adjustment for age, sex, smoking, previous cardiovascular disease and lipid status, carotid intima-media thickness failed to predict any cardiovascular event, whereas carotid plaques tended (P = 0.056) to predict the risk of cardiovascular death or myocardial infarction. Femoral intima-media thickness (P < 0.01) and plaques (P < 0.05) were also related to the risk of revascularization after adjustments. CONCLUSIONS: Carotid and femoral vascular changes were differently related to cardiovascular events. Carotid intima-media thickness was a weak predictor of events, whereas femoral intima-media thickness predicted revascularization. Plaques in the carotid artery were related to cardiovascular death or non-fatal myocardial infarction, whereas plaques in the femoral artery were related to revascularization. Evaluations of plaques provided better prediction than assessments of intima-media thickness in patients with stable angina.

Prognostic implications of results from exercise testing in patients with chronic stable angina pectoris treated with metoprolol or verapamil. A report from the Angina Prognosis Study In Stockholm (APSIS).

AIMS: To evaluate the prognostic implications of results from exercise testing, and of antianginal treatment among patients with chronic stable angina pectoris. MATERIAL AND METHODS: Out of 809 patients in the Angina Prognosis Study In Stockholm (APSIS), 731 (511 men) performed evaluable exercise tests before and after 1 month on double-blind treatment with metoprolol or verapamil. During a median follow-up of 40 months, 32 patients suffered a cardiovascular death and 29 a non-fatal myocardial infarction. RESULTS: Prognostic implications of results from exercise tests were assessed in a multivariate Cox model which included sex, previous myocardial infarction, hypertension and diabetes mellitus. Maximal ST-segment depression, especially if >/=2 mm and occurring after exercise, as well as exercise duration independently predicted cardiovascular death. Similar results were obtained for the combined end-point of cardiovascular death+myocardial infarction. Among patients with a positive exercise test at baseline, verapamil reduced the maximal ST-depression more markedly than metoprolol (P<0. 01). However, when the treatment given and treatment effects on ST-segment depression were added to the Cox model, no impact on prognosis could be detected for either cardiovascular death alone or combined with myocardial infarction. Anginal pain carried no prognostic information. CONCLUSION: Marked ST-segment depression during and after exercise, and a low exercise capacity independently predicted an adverse outcome in patients with stable angina pectoris, whereas anginal symptoms had no predictive value. Short-term treatment effects on ischaemia did not seem to influence prognosis. Post-exercise ischaemia should be examined carefully when evaluating patients with stable angina pectoris.

Inflammatory and hemostatic markers in relation to cardiovascular prognosis in patients with stable angina pectoris. Results from the APSIS study. The Angina Prognosis Study in Stockholm.

Increased inflammatory activity and platelet activation have been associated with an increased risk of cardiovascular (CV) events in epidemiological studies, but their prognostic importance in patients with stable angina pectoris is less well established. The Angina Prognosis Study in Stockholm (APSIS), comprised 809 patients (2766 patient years) with stable angina pectoris on double-blind treatment with verapamil or metoprolol. Plasma levels of fibrinogen and orosomucoid (an acute phase reactant), white blood cell counts (WBC), platelet counts and the urinary excretion of beta-thromboglobulin (reflecting platelet secretion), were related to the risk of CV death (n=36), non-fatal myocardial infarction (MI) (n=30) or revascularization (n=99) in a subgroup of 782 patients. Verapamil and metoprolol had only minor effects on the inflammatory variables. In multivariate Cox regression analyses (adjusted for previous MI, hypertension, diabetes mellitus and smoking), fibrinogen and WBC were independent predictors of CV death or non-fatal MI, as well as the risk of revascularization. Orosomucoid did not carry any independent information. Platelet counts and urinary beta-thromboglobulin were not significantly related to CV prognosis. The treatment given did not significantly influence the prognostic impact of either fibrinogen or WBC. Fibrinogen and WBC were independent predictors of CV death or non-fatal MI as well as disease progression leading to revascularization in patients with stable angina pectoris. As fibrinogen is also an acute-phase reactant, the present findings indicate that inflammatory activity is involved in disease progression in stable angina pectoris.

Prognostic implications of ambulatory myocardial ischemia and arrhythmias and relations to ischemia on exercise in chronic stable angina pectoris (the Angina Prognosis Study in Stockholm [APSIS]).

The prognostic significance of ambulatory ischemia, alone and in relation to ischemia during exercise was assessed in 686 patients (475 men) with chronic stable angina pectoris taking part in the Angina Prognosis Study In Stockholm (APSIS), who had 24-hour ambulatory electrocardiographic registrations and exercise tests at baseline (n = 678) and after 1 month (n = 607) of double-blind treatment with metoprolol or verapamil. Ambulatory electrocardiograms were analyzed for ventricular premature complexes and ST-segment depression. During a median follow-up of 40 months, 29 patients died of cardiovascular (CV) causes, 27 had a nonfatal myocardial infarction, and 89 underwent revascularization. Patients with CV death had more episodes (median 5 vs. 1; p<0.01) and longer median duration (24 vs. 3 minutes; p<0.01) of ST-segment depression than patients without events. For those who had undergone revascularization, the duration was also longer (12 vs. 3 minutes; p<0.05). In a multivariate Cox model including sex, history of previous myocardial infarction, hypertension, and diabetes, the duration of ST-segment depression independently predicted CV death. When exercise testing was included, ambulatory ischemia carried additional prognostic information only among patients with ST-segment depression > or =2 mm during exercise. When the treatment given and treatment effects on ambulatory ischemia were added to the Cox model, no significant impact on prognosis was found. Ventricular premature complexes carried no prognostic information. Thus, in patients with stable angina pectoris, ischemia during ambulatory monitoring showed independent prognostic importance regarding CV death. Ambulatory electrocardiographic monitoring and exercise testing provide complementary information, but only among patients with marked ischemia during exercise. Treatment reduced ambulatory ischemia, but the short-term treatment effects did not significantly influence prognosis.

Ischaemia during exercise and ambulatory monitoring in patients with stable angina pectoris and healthy controls. Gender differences and relationships to catecholamines.

AIMS: To evaluate signs of ischaemia and ventricular arrhythmias in relation to gender and sympathoadrenal activity in patients with stable angina pectoris and healthy controls. MATERIAL AND METHODS: 809 patients (248 females) with stable angina pectoris, and 50 matched healthy controls performed an exercise test and an ambulatory ECG recording. Catecholamines were measured in plasma before and immediately after exercise, and in urine during ambulatory ECG. RESULTS: Male and female patients showed similar frequencies of ST-depression, similar blood pressure and catecholamine responses on exercise testing. Females had higher heart rates and were more prone towards silent ischaemia. The healthy controls exercised longer and showed greater adrenaline responses. During ambulatory ECG, the two genders had similar duration of ST-depression, but males had more premature ventricular complexes. Females excreted more noradrenaline, and had higher minimal and maximal heart rates. Premature ventricular complexes were equally common among patients and controls, but controls had greater catecholamine excretion. Maximal ST-depression during exercise was positively related to the duration of ST-depression during ambulatory ECG for both genders. Exercise time until ST-depression was inversely related to the duration of ST-depression during ambulatory ECG among male patients only. Catecholamine responses during exercise testing were more closely correlated to time until chest pain than to signs of ischaemia. CONCLUSION: Mechanisms behind myocardial ischaemia and arrhythmias may differ in male and female patients, as females seem to be more prone towards silent ischaemia. Ischaemia on exercise correlated to ambulatory ischaemia among males only.

Cardiovascular prognosis in relation to apolipoproteins and other lipid parameters in patients with stable angina pectoris treated with verapamil or metoprolol: results from the Angina Prognosis Study in Stockholm (APSIS).

Relationships between apolipoproteins and other lipid parameters and cardiovascular (CV) prognosis were evaluated in the Angina Prognosis Study In Stockholm (APSIS). Out of 809 patients with stable angina pectoris, lipid variables were obtained in 786 patients at baseline, and after one month's double-blind treatment with metoprolol or verapamil, to evaluate treatment effects on these lipid variables. During a median follow-up time of 3.3 years (2663 patient years), 37 patients suffered a CV death, 30 suffered a non-fatal myocardial infarction (MI) and 100 underwent a revascularization. Apolipoprotein (apo) A-I, high-density lipoprotein cholesterol and triglycerides were predictors of CV death or non-fatal MI in univariate analyses, but only apo A-I remained as an independent predictor in multivariate analyses. All lipid variables except low density lipoprotein cholesterol were related to the risk of revascularization in univariate analyses, but only apo A-I and apo B were independent predictors of such events. Triglycerides were weakly, but not independently, associated with prognosis. Verapamil and metoprolol had differential short-term effects on lipids, with a shift towards a more atherogenic profile in metoprolol treated patients. However, there was no significant impact of the treatment given, or of these treatment effects on the risk of CV events. Results of the present study suggest that apolipoprotein levels were better predictors of CV events than other lipid parameters in patients with stable angina pectoris.

Fibrinolytic variables and cardiovascular prognosis in patients with stable angina pectoris treated with verapamil or metoprolol. Results from the Angina Prognosis study in Stockholm.

BACKGROUND: Disturbed fibrinolytic function may influence the progression of coronary atherosclerosis and contribute to thrombotic cardiovascular (CV) events. METHODS AND RESULTS: In the Angina Prognosis Study in Stockholm (APSIS), patients with stable angina pectoris were studied prospectively during double-blind treatment with metoprolol or verapamil. Various measures of fibrinolytic function were studied in 631 (of 809) patients. During a median follow-up time of 3.2 years (2132 patient-years), 32 patients suffered a CV death, 21 had a nonfatal myocardial infarction (MI), and 77 underwent revascularization. Plasma levels of tissue plasminogen activator (TPA) activity and antigen (ag), plasminogen activator inhibitor (PAI-1) activity at test, and TPA responses to exercise were determined at baseline and after 1 month's treatment and were related to subsequent fatal and nonfatal CV events. Univariate Cox regression analysis revealed that elevated levels of TPA-ag at rest (P < .05), high PAI-1 activity (P < .05), and low TPA-ag responses to exercise (P < .05) were associated with increased risk of subsequent CV death. After adjustment for baseline risk factors, TPA-ag independently predicted CV death or MI. In addition, PAI-1 activity independently predicted CV death or MI in male patients. Verapamil treatment was associated with a 10% decrease of TPA-ag levels and metoprolol treatment with a 2% increase (P < .001 for treatment difference). CONCLUSIONS: Plasma TPA-ag levels at rest, and among male patients PAI-1 activity as well, independently predict subsequent CV death or MI in patients with stable angina pectoris.

Haemostatic markers, inflammatory parameters and lipids in male and female patients in the Angina Prognosis Study in Stockholm (APSIS). A comparison with healthy controls.

OBJECTIVES: To investigate haemostatic markers (especially fibrinolysis), inflammatory parameters and lipids in patients with stable angina pectoris. Special attention was paid to differences between male and female patients, and to the reactivity to exercise or the diurnal variation of certain parameters. SUBJECTS: Eight hundred and nine patients (31% females) and a matched healthy control group (n = 50). RESULTS: The patients had signs of disturbed fibrinolysis, with elevated plasma levels of tissue plasminogen activator (tPA) antigen and plasminogen activator inhibitor (PAI-1) activity at rest, and attenuated responses of tPA antigen and activity to exercise. Elevated levels of fibrinogen, white blood cell counts and orosomucoid were found, suggesting increased inflammatory activity, as well as a more disturbed lipid profile (higher triglycerides and lower HDL cholesterol levels) than among controls. Female patients had higher HDL cholesterol and lower triglyceride levels than male patients, but higher platelet counts and signs of enhanced platelet activity (beta-thromboglobulin excretion). In addition, female patients had lower white blood cell counts, suggesting lesser inflammatory activity. CONCLUSIONS: Patients with stable angina pectoris have signs of markedly disturbed fibrinolysis both at rest and in response to exercise, as well as signs of enhanced inflammatory activity and dyslipidemia. The observed sex differences suggest that male patients with stable angina pectoris may have a more lipid-related disease, whereas it may be more dependent on platelet function in females.

Age and gender differences in left ventricular function among patients with stable angina and a matched control group. A report from the Angina Prognosis Study in Stockholm.

To assess left ventricular systolic and diastolic function, M-mode (n = 675) and transmitral Doppler echocardiography (n = 358) were performed in patients with stable angina pectoris and compared with 50 matched healthy controls. Left ventricular fractional shortening (FS) was significantly lower in male than in female patients (32 +/- 7 vs. 35 +/- 7%, p < 0.001). A history of heart failure was as frequent in men (6%) as in women (6%), but left ventricular systolic dysfunction was more frequent in men than in women (25 vs. 12%, p < 0.005). The ratio of early/late diastolic peak flow velocity (E/A ratio) was significantly lower, indicating diastolic dysfunction, in female patients with clinical heart failure than in those without (0.79 +/- 0.25 vs. 1.02 +/- 0.3, p < 0.05). No such difference was found in male patients. Inverse relationships were found between age and E/A ratio in both controls (r = -0.45, p < 0.001) and angina patients (r = -0.44, p < 0.001). Thus, despite similar frequency of clinical heart failure, left ventricular systolic dysfunction was more common in men than in women with stable angina.

Effects of metoprolol vs verapamil in patients with stable angina pectoris. The Angina Prognosis Study in Stockholm (APSIS)

OBJECTIVE: To study long-term treatment effects of metoprolol or verapamil on combined cardiovascular end points and psychological variables in patients with stable angina pectoris. DESIGN: Randomized, double-blind, double-dummy trial. PATIENTS: The study included 809 patients under 70 years of age with stable angina pectoris. The mean age of the patients was 59 +/- 7 years and 31% were women. Exclusion criteria were myocardial infarction within the previous 3 years and contraindications to beta-blockers and calcium antagonists. The patients were followed between 6 and 75 months (median 3.4 years and a total of 2887 patient years). INTERVENTION: The patients were treated with either metoprolol (Seloken ZOC 200 mg o.d.) or verapamil (Isoptin Retard 240 b.i.d.). Acetylsalicylic acid, ACE inhibitors, lipid lowering drugs and long acting nitrates were allowed in the study. END POINTS: Death, non-fatal cardiovascular events including acute myocardial infarction, incapacitating or unstable angina, cerebrovascular or peripheral vascular events. Psychological variables reflecting quality of life i.e. psychosomatic symptoms, sleep disturbances and an evaluation of overall life satisfaction. RESULTS: Combined cardiovascular events did not differ and occurred in 30.8% and 29.3% of metoprolol and verapamil treated patients respectively. Total mortality in metoprolol and verapamil treated patients was 5.4 and 6.2%, respectively. Cardiovascular mortality was 4.7% in both groups. Non-fatal cardiovascular events occurred in 26.1 and 24.3% of metoprolol and verapamil-treated patients, respectively. Psychosomatic symptoms and sleep disturbances were significantly improved in both treatment groups. The magnitudes of change were small and did not differ between treatments. Life satisfaction did not change on either drug. Withdrawals due to side effects occurred in 11.1 and 14.6% respectively. CONCLUSION: This long term study indicates that both drugs are well tolerated and that no difference was shown on the effect on mortality, cardiovascular end points and measures of quality of life.

Primary prevention in patients with coronary heart disease: the APSIS study.

Symptomatic treatment of patients with angina pectoris is well established and consists of nitrates, calcium antagonists, or beta-blockers. All these drugs improve symptomatology and reduce signs of ischemia on exercise test or long-term electrocardiogram recordings. It is not known, however, whether these drugs also improve prognosis. The only drug shown to improve prognosis is aspirin. In order to study the prognostic effect of calcium antagonists and beta-blockers, these two drugs were compared in the APSIS study.