Lennart Forslund

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.

Favourable long term prognosis in stable angina pectoris: an extended follow up of the angina prognosis study in Stockholm (APSIS)

Objective: To evaluate the long term prognosis of patients with stable angina pectoris. Design: Registry based follow up (median 9.1 years) of patients participating in the APSIS (angina prognosis study in Stockholm), which was a double blind, single centre trial of antianginal drug treatment. Patients: 809 patients (31% women) with stable angina pectoris < 70 (mean (SD) 59 (7) years at inclusion) and an age and sex matched reference population from the same catchment area. Interventions: Double blind treatment with metoprolol or verapamil during 3.4 years (median), followed by referral for usual care with open treatment. Main outcome measures: Cardiovascular (CV) death and non-fatal myocardial infarction (MI) in the APSIS cohort and total mortality in comparison with reference subjects. Results: 123 patients died (41 MI, 36 other CV causes) and 72 had non-fatal MI. Mortality (19% v 6%, p<0.001) and fatal MI (6.6% v 1.6%, p < 0.001) were increased among male compared with female patients. Diabetes, previous MI, hypertension, and male sex independently predicted CV mortality (p < 0.001). Diabetes greatly increased the risk in a small subgroup of female patients. Male patients had higher mortality than men in the reference population during the first three years (cumulative absolute difference 3.8%) but apparently not thereafter. Female patients had similar mortality to women in the reference population throughout the 9.1 years of observation. Conclusions: Female patients with stable angina had similar mortality to matched female reference subjects but male patients had an increased risk. Diabetes, previous MI, hypertension, and male sex were strong risk factors for CV death or MI.

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.

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.

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 months 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.

The influence of structured information and monitoring on the outcome of asthma treatment in primary care: a cluster randomized study.

Background: In clinical trials of asthma, the outcomes are often good, but when the same treatment regimens are implemented in primary care, equally good results are not obtained. Objective: To investigate if addition of structured patient information and monitoring by an asthma diary in primary care improves asthma control. Methods: 141 patients from 19 primary care centres were studied. The centres were randomised to a standard care group or to an intervention group. The intervention group received structured written and oral information about asthma and asthma medication, and were instructed to keep an asthma diary. The primary outcome was asthma control as assessed by the Asthma Control Questionnaire. Secondary outcomes were costs of asthma medication, the Mini Asthma Quality of Life Questionnaire score and lung function. Results: Asthma Control Questionnaire score changes differed between the study groups (p < 0.05). In the intervention group, these changes (M = –0.45) in asthma control were close to clinical significance (minimal important difference ≈0.5). Both groups improved in disease-specific quality of life scores. For the intervention group, which changed the most (p < 0.05), the change exceeded the threshold for the minimal important difference (0.5). The costs of medications increased significantly in the intervention group, where adjustments of medication were made more often than in controls. Conclusion: Disease-specific quality of life of asthma patients could be improved by adding structured information and monitoring by diary to standard care.

Long-term stability of heart rate variability in chronic stable angina pectoris, and the impact of an acute myocardial infarction.

Background:  Heart rate variability (HRV) reflects the balance between cardiac parasympathetic and sympathetic autonomic influences. Reduced HRV has adverse prognostic implications. The time course for changes in HRV over prolonged periods of time and the influence of an acute coronary event on HRV are not well established.

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.

Differential index: a simple time domain heart rate variability analysis with prognostic implications in stable angina pectoris.

Objectives: To examine the usefulness of time domain heart rate variability (HRV) measurements by a simple graphical method, the differential index (DI), in prognostic assessments of patients with chronic stable angina pectoris. Methods: HRV measurements in the time domain by DI were compared to conventional measurements of standard deviation of all normal-to-normal intervals (SDNN), percent of differences between adjacent normal RR intervals >50 ms (PNN50) and square root of the mean of the sum of squares of differences between adjacent normal RR intervals (RMSSD) from 24-hour ambulatory electrocardiographic recordings in 678 patients in the Angina Prognosis Study in Stockholm. The patients received double-blind treatment with metoprolol or verapamil. Main outcome measures were cardiovascular death or non-fatal myocardial infarction during follow-up (median 40 months). Results: Patients suffering cardiovascular death (n = 30) had lower DI, SDNN and PNN50 (all p < 0.001). In a multivariate Cox model, DI below median independently predicted cardiovascular death (p = 0.002), as did SDNN (p = 0.016) and PNN50 (p = 0.030), but not RMSSD (p = 0.10). The separation of survival curves was most pronounced and specificity was slightly better with DI. DI and PNN50 increased with metoprolol but not verapamil treatment. Short-term treatment effects were not related to prognosis. Conclusions: Low time domain HRV carries independent prognostic information regarding cardiovascular death in stable angina pectoris. The simple DI method provided equally good or better prognostic information than conventional, more laborious HRV methods.

Reflections on the regulation of the Polypill

The Polypill for prevention of cardiovascular disease was first proposed in 2003 and results of the first trials are eagerly anticipated. Regulatory agencies face the challenge of deciding which studies should be requested to meet reasonable demands regarding efficacy and safety of the Polypill in the intended (high-risk) target population. In this Viewpoint, Dr Forslund highlights the important issues that should be considered when generating these regulatory recommendations.