Optimal intensity of oral anticoagulant therapy after myocardial infarction.

OBJECTIVES: This study attempted to determine the optimal intensity of anticoagulant therapy in patients after myocardial infarction. BACKGROUND: Treatment with oral anticoagulant therapy entails a delicate balance between over- (risk of bleeding) and under-anticoagulation (risk of thromboemboli). The optimal intensity required to prevent the occurrence of either event (bleeding or thromboembolic) is not known. METHODS: A method was used to determine the optimal intensity of anticoagulant therapy by calculating incidence rates for either event associated with a specific international normalized ratio. The numerator included events occurring at given international normalized ratios, and the denominator comprised the total observation time. RESULTS: The study population included 3,404 myocardial infarction patients enrolled in the ASPECT (Anticoagulants in the Secondary Prevention of Events in Coronary Thrombosis) trial. Total treatment was 6,918 patient-years. Major bleeding occurred in 57 patients (0.8/100 patient-years), and thromboembolic complications in 397 (5.7/100 patient-years). The incidence of the combined outcome (bleeding or thromboembolic complications) with international normalized ratio <2 was 8.0/100 patient-years (283 events in 3,559 patient-years), with international normalized ratios between 2 and 3, 3.9/100 patient-years (33 events in 838 patient-years); 3.2/100 patient-years (57 events in 1,775 patient-years) for international normalized ratios between 3 and 4; 6.6/100 patient-years (37 events in 564 patient-years) for international normalized ratios between 4 and 5; and 7.7/100 patient-years (14 events in 182 patient-years) for international normalized ratios >5. After adjustment for achieved international normalized ratio levels, significant predictors were higher levels of systolic blood pressure and age. CONCLUSIONS: If equal weight is given to hemorrhagic and thromboembolic complications, these results suggest that the optimal intensity of long-term anticoagulant therapy for myocardial infarction patients lies between 2.0 and 4.0 international normalized ratio, with a trend to suggest an optimal intensity of 3.0 to 4.0.

Effects of nitrendipine and enalapril on left ventricular mass in patients with non-insulin-dependent diabetes mellitus and hypertension.

OBJECTIVE: To compare the effects of a calcium antagonist (nitrendipine) and an angiotensin converting enzyme inhibitor (enalapril) with those of placebo on left ventricular mass in patients with non-insulin-dependent diabetes mellitus and hypertension. DESIGN: A double-blind randomized, placebo-controlled trial. SETTING: General practitioners referred patients to the trial physician. PATIENTS: The study population comprised 121 patients with non-insulin-dependent diabetes mellitus. Inclusion criteria for blood pressure were diastolic blood pressure 90-115 mmHg and systolic blood pressure < or = 200 mmHg, while subjects were not being administered blood-pressure-lowering drugs for 3 weeks. INTERVENTION: Patients were randomly allocated to receive nitrendipine (n = 40), enalapril (n = 40) or placebo (n = 41). The treatment period was 48 weeks. MAIN OUTCOME MEASURES: The effect of nitrendipine was defined as the difference in change in left ventricular mass index from baseline between nitrendipine treatment and placebo after 48 weeks of treatment. The effects of nitrendipine compared with that of enalapril and of enalapril compared with placebo were defined similarly. Left ventricular mass was measured by M-mode echocardiography. RESULTS: Use of nitrendipine and enalapril led to significant and almost identical reductions in systolic and diastolic blood pressures. During 48 weeks left ventricular mass index decreased by 5% for patients in the nitrendipine group (decrease by 12 g/m2, 95% confidence interval 1-23), remained about the same for patients in the enalapril group (decrease by 1 g/m2, 95% confidence interval decrease by 10 to increase by 9) and increased by 9% for patients in the placebo group (increase by 9 g/m2, 95% confidence interval 2-16). CONCLUSION: These results indicate that administration of nitrendipine to patients with non-insulin-dependent diabetes mellitus and hypertension reduces left ventricular mass index. Enalapril appears not to induce regression, but perhaps prevents progression with an effect that is intermediate between those of nitrendipine and placebo.

The incidence of deep venous thrombosis in patients with an acute myocardial infarction treated with acenocoumarol or indobufen.

In a randomized double blind clinical trial, we compared indobufen, an antiplatelet drug, with acenocoumarol for the prevention of deep venous thrombosis (D.V.T.) in patients with acute myocardial infarction. Therapy was started on admission and continued for 10 days. All patients were screened daily with impedance plethysmography (I.P.G.) and 125I-fibrinogen leg scanning. Diagnosis of D.V.T. was made when either one or both tests became positive. 74 patients were randomized to treatment with indobufen (200 mg b.i.d.) and 76 patients to acenocoumarol (controlled by thrombotest). The incidence of venous thrombosis in patients with indobufen was 11% and in those treated with acenocoumarol 9%. Major bleeding was observed in 2 patients treated with acenocoumarol. In the indobufen group, no bleeding complications or other serious side-effects were observed. The majority of patients developed thrombosis after the first week of admission. For patients with and without thrombosis, there was no significant difference between the two treatment groups concerning the age, the coronary prognostic index, the maximum C.P.K. value, mobility, incidence of congestive heart failure and the site or extent of the infarct. In this study no clinical or laboratory (fibrinogen, platelet count and anti-thrombin III) parameter, either alone or in combination, was of predictive value for the development of D.V.T. It can be concluded that indobufen appears to be as good as acenocoumarol for the prevention of D.V.T. in patients with acute myocardial infarction. Because it is safe and easy to administer, indobufen seems to be preferable. Prophylaxis is required for at least 10 days.

Home-diagnosis of deep venous thrombosis with impedance plethysmography.

In order to assess the value of I.P.G. for the diagnosis of D.V.T. in general practice, an I.P.G. was carried out by a skilled technician in 255 consecutive patients with suspected D.V.T. at home. Ascending venography was carried out in 185 of these patients. In addition, blood for assay of AT III, platelet count, fibrinogen, a2-antiplasmin, ethanol gelation test and spontaneous platelet aggregation was collected at the time the I.P.G. was performed. In 61 patients (33%) venography showed the presence of D.V.T., and was negative in the remaining 124 patients. I.P.G. was positive in 51 of the 61 patients with D.V.T., a sensitivity of 84%. I.P.G. was normal in 115 of the 124 patients with a negative venogram, a specificity of 93%. The sensitivity of the I.P.G. for proximal vein thrombosis was 92% and for calf vein thrombosis 68%. Mean a2-antiplasmin concentration was significant (p less than 0.05) lower (101 +/- 15%, mean +/- SD) in patients with D.V.T. compared with patients with a normal venogram (107 +/- 11%, mean +/- SD). No differences between the two groups were observed in the other coagulation parameters assayed, and none was of diagnostic value, either alone or in combination with I.P.G. This study shows that I.P.G. is of potential value for the home diagnosis of D.V.T., in particular proximal vein thrombosis. This is potentially clinically useful, because these thrombi are thought to carry a high risk for pulmonary embolism.

Assessment of therapeutic quality control in a long-term anticoagulant trial in post-myocardial infarction patients.

Various methods have been described to evaluate efficacy of anticoagulant therapy using the international normalized ratio (INR). We compared the following approaches: (1) total INR's or the most recent measurement; (2) percent time within therapeutic range, with INR changing directly or halfway between visits; and (3) total observation time assuming INR changing linearly. The study population comprised 1700 post myocardial infarction patients. Treatment comprised 3725 patient-years. There were 61,471 INR assessments with target therapeutic level of 2.8-4.8. Acenocoumarol as well as phenprocoumon were employed. Therapeutic achievement in the first months of treatment was low: less than 60% of INR's were in range. Treatment stabilized after 6 months. Patients on acenocoumarol were within range 70% of the time compared to 80% for phenprocoumon. Method 3 is preferred because it incorporates time and is capable of calculating incidence rates at different INR levels. Our findings call for an urgent improvement of standard of anticoagulant control in the first months following commencement of treatment.

A double blind three center clinical trial on the short-term efficacy of 0-(beta-hydroxyethyl)-rutosides in patients with post-thrombotic syndrome.

A multi-centre, double blind randomized clinical trial was designed to assess the efficacy and safety of orally administered 0-(beta-hydroxyethyl)-rutosides (HR) capsules in the treatment of 101 patients with post-thrombotic syndrome. Seventeen patients were excluded from the analysis for violation of the study protocol, 41 received HR capsules (1,200 mg/day) and 43 placebo. Mean follow-up scores at the 4th and 8th week show that the HR patients displayed an improved state of tiredness as compared to the placebo's. The mean circumference of the calf for the HR group decreased from 390 (+/- 33) mm at visit one to 382 (+/- 33) mm at visit three, with a mean circumference reduction of 8.7 (+/- 8) mm, compared to a steady placebo circumference of 387 (+/- 31) mm at all 3 visits with a mean circumference reduction of only 2 mm (+/- 9). The estimated treatment effect at week 8 was -6.7 mm, 95% confidence interval (-10.3, -3.0). The mean circumference of the ankle, decreased from 243 (+/- 20) mm to 238 (+/- 20) mm at the 4th week, contrasted with a constant placebo circumference of 241 (+/- 22) mm at both visits. The estimated treatment effect at week 4 was -5.4 mm, 95% confidence interval (-10.2, -0.6). However, at week 8, the estimated treatment effect was only -3.4 mm, 95% confidence interval (-8.6, +1.8). In conclusion, HR capsules may show an improvement in the clinical symptoms and may show a mean circumference reduction of the calf and ankle at the 8th week, in patients with post-thrombotic syndrome.

Is quantitative determination of fibrin(ogen) degradation products and thrombin-antithrombin III complexes useful to diagnose deep venous thrombosis in outpatients?

We studied the diagnostic value of recently introduced ELISA's for the determination of thrombin-antithrombin III (TAT) complexes, fibrin degradation products (FbDP), fibrinogen degradation products (FgDP) and total degradation products (TDP) for deep venous thrombosis (DVT) in plasma of 239 consecutive outpatients, suspected for DVT by their family doctor. DVT was confirmed by impedance plethysmography in 60 patients. Using the 95th percentile range of 42 healthy volunteers the sensitivity for the detection of DVT was: 37% for TAT, 95% for TDP, 92% for FbDP and 90% for FgDP. Specificity was: 88% for TAT, 16% for TDP, 20% for FbDP and 25% for FgDP. We conclude that these assays are of little value in the diagnosis of DVT in outpatients.

A new computerized impedance plethysmograph: accuracy in the detection of proximal deep-vein thrombosis in symptomatic outpatients.

Because of the lack of specificity of the clinical diagnosis it is appropriate in patients with clinically suspected deep-vein thrombosis to apply an objective test before starting anticoagulant treatment. Impedance plethysmography is a highly accurate technique for the detection of proximal-vein thrombosis with a reported sensitivity and specificity of 93 and 97%, respectively. In all previous reported evaluations of impedance plethysmography an apparatus which was developed in 1971 was used. A new computerized impedance plethysmography, using a novel device to measure impedance, was blindly compared against venography in 443 consecutive outpatients with clinically suspected deep-vein thrombosis. In the first phase of the study the computerized impedance plethysmography test results of 242 symptomatic patients were used to develop a discriminant line. Subsequently, this discriminant line was validated in the second phase of the study in another 201 symptomatic patients. The combined sensitivity and specificity of these two phases for proximal-vein thrombosis was 91% [95% confidence interval (CI), 86 to 94%] and 94% and (95% CI, 90 to 96%), respectively, which compares favourably with impedance plethysmography. It is concluded that computerized impedance plethysmography is a simple, portable, non-invasive technique with a high accuracy for the detection of proximal vein thrombosis. However, before computerized impedance plethysmography can be used as the only test in the diagnosis of deep-vein thrombosis, the safety of withholding anticoagulant treatment to patients with repeated normal computerized test results should be assessed during long-term follow-up studies.

Efficiency optimization of the selection period in therapeutic trials.

To determine eligibility for a (randomized) clinical trial, measuring the inclusion and exclusion criteria can be extended over a period of time. During this period, known as the selection period, a patient is repeatedly examined at certain time intervals. This study describes an approach for optimizing the efficiency of the selection period. Efficiency is defined as the costs of randomizing one patient. The objective is to construct prediction models based on data obtained early in the selection period to predict subsequent exclusions. A prediction model increases the efficiency if after its application the costs per randomization are lower. The approach is illustrated using data from the selection period of the Rotterdam Cardiovascular Risk Intervention (ROCARI) trial which was composed of five consecutive patient visits. At each visit, data to determine eligibility was obtained. We found that logistic regression models based on data of the first and second visit could predict exclusions during the third visit. Application of the prediction models suggested that in this particular trial the costs per randomization would decrease by $52. As the initial costs per randomization were $1444, there would be a 3.6% (52/1444) savings in recruitment costs under the prediction models, accounting for a savings of more than $450,000. We conclude that the use of data obtained early in a selection period can predict subsequent exclusions, and therefore could increase the efficiency of such a period. The approach could be applied to data obtained in a pilot study as well as data obtained in the beginning of a prolonged intake period.

The value of adding thermographic leg scanning to impedance plethysmography in the detection of deep vein thrombosis.

The clinical value of adding thermographic leg scanning to impedance plethysmography was evaluated and compared in 52 patients with clinically suspected deep venous thrombosis. Both tests were performed on the day of referral and phlebography within 72 hours. The sensitivity of thermography was 83%, the specificity 41% and the accuracy 61%. In comparison IPG had a sensitivity of 83%, a specificity of 96% and an accuracy of 90% The combination of thermography and IPG showed a sensitivity of 92%, a specificity of 41% and an accuracy of 65%. It is concluded that the addition of thermography to IPG is of no clinical value.

Characteristics and prognosis of non-participants of a multi-centre trial of long-term anticoagulant treatment after myocardial infarction.

Participants of a randomised trial may differ from eligible non-participants as a result of selection. We studied the distribution of prognostic factors and survival in eligible patients of a multi-centre trial of long-term oral anticoagulant treatment after myocardial infarction. All hospital survivors of myocardial infarction in one participating clinical centre of a multi-centre, randomised, double-blind, placebo-controlled trial of long-term anticoagulant treatment after myocardial infarction were screened for entry criteria. Subsequently, prognostic factors and survival of participants were compared with eligible but not randomised patients. The 350 participants were younger and were more often of male gender and more often smokers compared with 587 non-participants. Non-participants had more frequently suffered a previous myocardial infarction and were treated more often with diuretics and ACE-inhibitors, suggesting a higher proportion of patients with chronic heart failure in this group. Age, previous myocardial infarction and the use of diuretics at discharge were independent predictors of mortality, consent showed no association. Our findings indicate that participants of a clinical trial have a better prognosis during the first years following myocardial infarction compared to eligible non-participants as a result of a higher prevalence of cardiovascular risk factors associated with mortality in the non-participants.

[Functioning of an Exercise electrocardiographic service for family physicians; a report of 498 patients]. / Het functioneren van een inspannings-elektrocardiografische service voor huisartsen; een beschrijving van 498 patiënten.

OBJECTIVE: In Rotterdam GPs have the possibility of requesting an exertion ECG for their patients from the Foundation Thrombosis Service and Physicians' Laboratory. A follow-up study was carried out in order to gain insight into the functioning of this service. PATIENTS AND METHODS: Over a period of three months, 266 GPs referred 498 patients to the service for an exertion ECG. The GPs received an enquiry form with questions on the referral and the functioning of the service. The patients were followed up for two weeks in connection with any (cardiovascular) events and with the management by the GP. An ECG was regarded as positive if the ST showed a depression greater than or equal to 1.5 mm. RESULTS: None of the patients died during the period of the investigation. Of the patients with positive and with negative ECGs, 41% and 37%, respectively, had no more complaints, 40% and 28% the same complaints, and 3% and 0.5% more complaints. Of the patients with a negative ECG (n = 439), 3.9% were referred to a cardiologist. If no ECG had been made, this proportion would have been 39%. CONCLUSION: The Foundation Thrombosis Service and Physicians' Laboratory Rotterdam provides an essential contribution to GPs' decision making concerning referral of patients with vague cardiac complaints to a cardiologist.

[Adjustment to insulin of patients with type II diabetes mellitus in primary care; good results at low cost]. / Instelling op insuline van patiënten met diabetes mellitus type II in de eerste lijn; goede resultaten bij geringe kosten.

OBJECTIVE: Comparison of costs and results of different treatment policies for patients with diabetes mellitus type II (NIDDM) starting on insulin. DESIGN: Retrospective study using literature control data. SETTING: Diabetes Centre Rotterdam (DCR). METHODS: The effects of home treatment by the DCR were studied during one year in 52 NIDDM patients by measurement of glycosylated haemoglobin (HbA1c) values. These effects were compared with literature data. Cost data of insulin treatment were calculated for the different policies. RESULTS: After one year of insulin treatment, the DCR patients had 'satisfactory' HbA1c levels according to international standards. In comparable patients treated at an outpatient clinic these values were 'poor'. Home treatment versus treatment at an outpatient clinic or during hospitalisation constituted a cost reduction of NFL 416 and NFL 2480 per patient respectively. CONCLUSION: Insulin treatment in NIDDM patients at home has at least the same effects on HbA1c values as obtained in patients treated at an outpatient clinic, and reduces costs.

[Antithrombotic treatment following acute ischemic heart disease: acetylsalicylic acid and (or) oral anticoagulants?; ASPECT-II, a new study]. / Antitrombotische behandeling na een acute ischemische hartziekte: acetylsalicylzuur en (of) orale anticoagulantia?; ASPECT-II, een nieuw onderzoek.

In order to compare the efficacy and safety of three regimens of long-term antithrombotic treatment in patients with acute ischaemic syndromes, a prospective, randomized, open-label, multicentre study is being conducted in which 60-70 Dutch hospitals will participate. Eligible patients discharged following hospitalization for acute myocardial infarction or unstable angina pectoris are randomly assigned to receive either (a) adjusted full intensity oral anticoagulation (target range: 3.0-4.0 International Normalised Ratio (INR), (b) low dose aspirin or (c) combined therapy of low dose aspirin and adjusted low intensity oral anticoagulation (target range INR: 2.0-2.5). It is planned to enroll 8,700 patients within three years. During an estimated mean follow-up of 2.5 years the evolutions of total mortality, non-fatal myocardial infarction, non-fatal stroke and major bleeding complication will be assessed.

Quality of secondary cardiovascular prevention in specialised care in the Netherlands: the SOLID study.

OBJECTIVE: To determine the extent to which Dutch patients with a history of cardiovascular disease and high cholesterol levels, treated in specialised care, are achieving low-cholesterol targets as defined by national guidelines. DESIGN: Hospital-based cohort study. SETTING: Practices of 41 hospital-based cardiologists and internists in the Netherlands. SUBJECTS: 7377 patients. RESULTS: Forty-one percent of the patients with an indication for secondary cardiovascular prevention by lipid-lowering drug treatment were receiving medication and were achieving cholesterol targets, 42% were receiving lipid-lowering medication but had cholesterol levels above target, 11% were not receiving treatment, and 5% had no recent lipid measurements. CONCLUSION: Compared with previous studies, the SOLID study shows that a relatively large percentage of the Dutch patients under specialised care with a history of cardiovascular disease and an indication for cholesterol-reducing therapy are currently being treated. A considerable proportion of the patients, however, are still not receiving optimal treatment and more than 10% are not being treated at all.

Prognostic significance of nonfatal myocardial reinfarction in survivors of a first infarction.

BACKGROUND: Patients who develop a reinfarction are at increased risk for subsequent reinfarctions and death. However, follow-up studies in these patients are rare. OBJECTIVE: The purpose of this study was to examine the risk of mortality after a first myocardial reinfarction and to determine the independent contribution of nonfatal reinfarction to the risk of subsequent mortality. METHODS: The prognostic value of nonfatal reinfarction was assessed in a large series (n=3097) of patients with a first myocardial infarction who participated in the ASPECT trial, comparing coumarin or matching placebo. RESULTS: A second myocardial infarction was documented in 299 patients (82% Q-wave infarctions), 45 (15%) of which were fatal. Of the 254 nonfatal reinfarctions, 31 patients (12%) died during subsequent follow-up. After adjustment for baseline characteristics, the relative risks of nonfatal reinfarction for subsequent cardiac mortality at one month were: 2.90 (1.49-5.64), at one year: 2.50 (1.47-4.23) and at three years: 2.71 (1.77-4.17). Rates of death or a second reinfarction in patients who did not undergo a revascularisation procedure after a first reinfarction were almost three times higher than in patients who did have PTCA or bypass surgery after a reinfarction (38% versus 14%; p<0.0001). CONCLUSION: This study population with three-year follow-up confirms that nonfatal reinfarction carries a strong and independent risk for recurrent reinfarction and subsequent mortality. Thus, prevention of reinfarction by intensive treatment might contribute in reduction of mortality.