Factorial trials in cardiology: pros and cons.
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Data Interpretation, Statistical↗
Biomedical subjects
J Lubsen
Publications and source records attributed to J Lubsen.
Exercise testing as outcome in congestive heart failure trials. Design considerations when interpreting results.
In addition to standard features of clinical trial design such as randomisation and double-blinding, sensitivity to drug effects is an important consideration when conducting exercise capacity trials in patients with heart failure. Two issues need to be addressed in this context. Firstly, it is important to enrol patients who are potential responders. Patients who have, for their age and sex, normal exercise capacity are unlikely to improve, even when given a drug that has a positive effect on exercise capacity. In addition, those patients who remain clinically stable following withdrawal of their previous drug therapy are unlikely to respond subsequently to an experimental drug with a similar mechanism of action. Secondly, failure to complete scheduled exercise tests during follow-up, prompting a 'per-protocol' analysis of results, may mask the drug's actual effect. To avoid this, an 'intention-to-treat' approach to data collection and analysis, with appropriate allowance made for missing test data, should be adopted.
Aged↗
Do non-potassium-sparing diuretics increase the risk of sudden cardiac death in hypertensive patients? Recent evidence.
Whether non-potassium-sparing diuretics (NPSD) increase the risk of sudden cardiac death in hypertensive patients has been vigorously debated. Diuretic-induced potassium or magnesium depletion leading to cardiac arrhythmias has been suggested as the underlying mechanism. A clear dose-response relationship between NPSD and the reduction in serum K+ exists. Data regarding serum Mg++ and intracellular K+ and Mg++ are too limited to allow conclusions. NPSD seem to increase the risk of ventricular arrhythmias among hypertensive patients with clinical evidence of heart disease, but the number of studies is small. The findings among patients without evidence of heart disease are less conclusive. The interpretation of the studies on electrolyte changes and arrhythmias following diuretic therapy is obscured by the fact that only a minority of studies included a randomly allocated placebo-treated control group. The large hypertension trials provide the strongest evidence that NPSD for hypertension may induce sudden death. Although blood pressure lowering may be expected to reduce the incidence of sudden cardiac death, the incidence in the NPSD group is similar to or even higher than that in the control group in 9 of 10 trials. We conclude that the beneficial effect of NPSD therapy for hypertension is partly offset by an excess risk of sudden death. Thus, alternative drugs, notably potassium-sparing diuretics or beta-blockers, could be preferred as antihypertensive drugs of first choice, although the efficacy of beta-blockers in older patients has recently been challenged.
Adult↗
Left ventricular systolic and diastolic function, and exercise capacity six to eight weeks after acute myocardial infarction. The DEFIANT Study Group. Doppler Flow and Echocardiography in Functional Cardiac Insufficiency: Assessment of Nisoldipine Therapy.
Echocardiographic and Doppler-derived measurements of left ventricular (LV) function at rest were examined as predictors of maximal bicycle exercise capacity in a homogeneous group of 115 patients with mild to moderate LV dysfunction (ejection fraction 22 to 56%, median 43%) participating in the DEFIANT study of nisoldipine after acute myocardial infarction. Although the relations were not exact, peak exercise work load 7 weeks after infarction correlated with measurements of diastolic LV function at rest. Exercise work load was inversely related to peak late diastolic transmitral blood flow velocity (A wave) (slope -86.6; 95% confidence interval -120.9 to -52.2) and directly to the E/A ratio (slope 20.5; 95% confidence interval 6.0 to 35.1). The relations between exercise work load and peak late diastolic flow velocity remained significant after correction for age, sex, heart rate at rest, and use of beta-blocking drugs or nisoldipine. There was no relation between peak exercise work load and peak early diastolic transmitral flow velocity (E wave), isovolumic relaxation period or deceleration time. Measurements of systolic LV function (LV end-diastolic and end-systolic volumes, and ejection fraction, stroke volume and cardiac index) were also not significant as predictors of exercise capacity.
Adult↗
Cardiovascular risk and all-cause mortality; a 12 year follow-up study in The Netherlands.
To assess the contribution of cardiovascular risk indicators to all-cause mortality, we used data from a follow-up study conducted in the Netherlands since 1975. Of 6,057 participants aged 20 years or over at the start of the study, 9.5% died during the 9 to 12 year follow-up period. Risk indicators independently related to all-cause mortality were age and diabetes mellitus in both sexes; pulse rate, smoking habits, antihypertensive drug use and a history of myocardial infarction most clearly in men; and body mass index and systolic blood pressure in women. A larger body mass index was associated with a gradual decrease in mortality probability. The risk of death for women in the highest quartile of body mass index (> 26.4 kg/m2) relative to those in the lowest quartile (< 21.9 kg/m2) was 0.56 (95% confidence limits 0.36 and 0.87). Serum cholesterol level showed no association with overall mortality. Risk functions were calculated to predict an individual's probability of dying within 11.5 years as a function of the level of cardiovascular risk indicators. Our findings suggest that the major cardiovascular risk indicators, apart from affecting cardiovascular morbidity and mortality, also influence all-cause mortality. Consequently, favourable changes in these characteristics might lead to an increase in life expectancy. The maximum individual benefit to be expected from these changes may be estimated using the risk functions derived from our data.
Adult↗
Prediction of mortality following hospital discharge after thrombolysis for acute myocardial infarction: is there a need for coronary angiography? European Cooperative Study Group.
The role of coronary angiography before hospital discharge after myocardial infarction was assessed in 1043 hospital survivors of the alteplase/placebo and the alteplase/PTCA trial of the European Cooperative Study Group. Forty-two of 1043 patients (4.0%) died after 1 to 489 days after predischarge coronary angiography. In survivors, follow-up ranged from 34 to 1106 days. In a stepwise multivariate regression model (Cox), use of diuretics and/or digitalis, a history of previous infarction and age exceeding 60 years were retained in the model with clinical data only. In addition, inability to perform exercise testing and less than 30 mmHg exercise-induced systolic blood pressure increase were selected by multivariate analysis. Large enzymatic infarct size, radionuclide left ventricular ejection fraction below 40%, and multivessel disease were also determinants of mortality after hospital discharge. The risk function, including coronary angiography, performed no better in late mortality prediction than functions based on clinical data and non-invasive testing. Patients without a history of previous infarction, not treated with diuretics and/or digitalis and with a systolic blood pressure increase of 30 mmHg or more during exercise had an excellent survival (98.6%) in the first year after hospital discharge, irrespective of whether symptoms of recurrent ischaemia occurred. This low risk group formed 47% of the total patient population and does not benefit from coronary angiography.
Analysis of Variance↗
QT interval variables from 24 hour electrocardiography and the two year risk of sudden death.
OBJECTIVE: To study the effects of variability in the duration of the QT interval corrected for heart rate (QTc) on the occurrence of sudden death. DESIGN: Nested case-referent study. SUBJECTS: Cohort of 6693 consecutive patients who underwent 24 hour electrocardiography and were followed up for two years. Risk implications of QTc interval variables were studied in patients without evidence of cardiac dysfunction or of an intraventricular conduction defect (104 died suddenly and 201 patients were randomly drawn from the study cohort). MAIN OUTCOME MEASURES: Mean QTc interval duration and variation in QTc duration over time correlated with occurrence of sudden death. RESULTS: Patients with a prolonged mean QTc over 24 hours (> or = 440 ms) had a 2.3 times (95% confidence interval 1.3 to 4.5) higher risk of dying suddenly than patients with a normal mean QTc (400-440 ms); patients with a shortened mean QTc (< 400 ms) also had a higher risk (relative risk 2.4 (1.4 to 4.3)). Patients with low (< 20 ms) and high (> or = 25 ms) long term variation in QTc duration had an increased risk of dying suddenly compared with those with intermediate variation (20-25 ms) (relative risks 2.2 (1.2 to 4.2) and 2.3 (1.4 to 4.2) respectively). The relative risks for low and high short term variation were not significantly raised. CONCLUSIONS: A prolonged and a shortened mean QTc interval over 24 hours was associated with a more than twofold risk of sudden death compared with intermediate mean QTc values (400-440 ms). Neither short nor long term variability in QTc had a distinct relation with the risk of sudden death.
Case-Control Studies↗
Contribution of the 24 hour electrocardiogram to the prediction of sudden coronary death.
BACKGROUND: Sudden coronary death is a major public health issue. The identification of patients at high risk should therefore be as efficient as possible. This study compares simple and more elaborate risk stratification procedures. METHODS: Risk functions for the prediction of sudden death were determined in a population of 6693 consecutive patients who had 24 hour electrocardiography for various indications. The functions were based on the clinical and electrocardiographical data on 245 patients who died suddenly during 2 year follow up and 467 patients randomly drawn from the total study population. RESULTS: The model based on history (age, sex, myocardial infarction, congestive heart failure, palpitation, syncope, use of diuretics, and use of nitrates), 12 lead electrocardiography (major intraventricular conduction defect, T wave abnormality, and ST depression > or = 0.05 mV), and standard rhythm analysis of 24 hour electrocardiography (ventricular tachycardia, frequent premature atrial complexes, sinus tachycardia (> 150 min-1), and atrial fibrillation) was almost as efficient in the prediction of sudden death as extended models that also contained information from exercise testing, echocardiography, ventriculography, and computer-aided re-analysis of 24 hour electrocardiography (QT and RR interval variability). CONCLUSIONS: These results indicate that additional information from advanced function tests does little to increase the efficiency of prediction of sudden coronary death over that of tests based on history, the standard 12 lead electrocardiogram, and 24 hour electrocardiography.
Cohort Studies↗
Heart rate variability from 24-hour electrocardiography and the 2-year risk for sudden death.
BACKGROUND: Low heart rate variability has been implicated as a risk factor for sudden death. However, no large epidemiological studies using sudden death as an outcome event have been reported. METHODS AND RESULTS: A total of 6,693 consecutive patients who underwent 24-hour ambulatory ECG were followed up for 2 years; of these, 245 patients died suddenly. Clinical data at the time of 24-hour ambulatory ECG were collected for all patients who died suddenly and for a random sample of 268 patients from the study cohort. In all patients in sinus rhythm with or without occasional supraventricular arrhythmias at the 24-hour ECG (193 patients who died suddenly and 230 patients from the sample), heart rate variability parameters were derived. Patients with low short-term RR interval variability (mean during 24 hours of per-minute standard deviations [SD] of RR intervals < 25 msec) had a 4.1-fold higher risk (95% confidence interval [CI], 2.6, 8.1) for sudden death than patients with high short-term variability (> or = 40 msec); after adjustment for age, evidence of cardiac dysfunction, and history of myocardial infarction, the relative risk was 2.6 (95% CI, 1.4, 5.1). The crude relative risk of long-term RR interval variability (SD during 24 hours of per-minute means of RR intervals < 8 msec) was 4.4 (95% CI, 2.6, 7.7); after adjustment for the same risk factors, it was 2.2 (95% CI, 1.2, 4.1). Patients with a minimum heart rate > or = 65 beats per minute had a double risk of sudden death compared with those with a minimum heart rate < 65 beats per minute (adjusted relative risk, 2.1; 95% CI, 1.3, 3.6). CONCLUSIONS: These findings support the theory that patients with low parasympathetic activity (low short-term RR interval variability) have an increased risk for sudden death independent of other risk factors.
Autonomic Nervous System↗
[Risk factors for the occurrence of recurrent convulsions following an initial febrile convulsion].
The results of a follow up study of 155 Dutch children who visited the emergency room of an urban paediatric hospital after experiencing their first febrile seizure are presented. Median follow up time was 38 months (range 27-60). Of these 155 initially untreated children 58 (37%) suffered at least one, 47 (30%) at least two and 27 (17%) at least three recurrent seizures. The recurrence hazard after any seizure was highest in the first six months, and dropped markedly after 6 months without seizures. The effect of the various postulated risk factors on the occurrence of any recurrent seizure and three or more recurrences was assessed. A first degree family history of febrile or nonfebrile seizures appears to be a predictor of multiple recurrences; an age of at least 30 months and a temperature of 40.0 degrees C or higher at the initial seizure are associated with a decreased risk. Several factors act together on the risk of recurrent seizures, sometimes in opposite directions. By considering the action of all relevant factors (age at onset, family history and features of the initial febrile seizure) subgroups of children with one year seizure recurrence rates as low as 15% and as high as 48% were identified.
Age Factors↗
Seizure recurrence after a first febrile seizure: a multivariate approach.
The results are presented of a follow-up study of 155 Dutch children after the first febrile seizure. Of these initially untreated children 37 per cent had had at least one, 30 per cent at least two and 17 per cent at least three subsequent seizures. The vulnerable period for recurrent seizures after the first febrile seizure was between 12 and 24 months, whereafter the risk was four to five times lower; after any seizure the risk was highest within the first six months, declining steadily after six months without seizures. A first-degree family history of any type of seizure predicted multiple recurrences; an age of at least 30 months and a temperature of greater than or equal to 40 degrees C at initial seizure were associated with reduced risk. Factors in combination influenced the risk of recurrent seizures, sometimes in opposite ways.
Body Temperature Regulation↗
Recombinant tissue-type plasminogen activator and immediate angioplasty in acute myocardial infarction. One-year follow-up. The European Cooperative Study Group.
BACKGROUND: The European Cooperative Study Group conducted two randomized trials in patients with suspected myocardial infarction to assess the effect of 100 mg single-chain recombinant tissue-type plasminogen activator (rt-PA, alteplase) on enzymatic infarct size, left ventricular function, morbidity and mortality relative to placebo (alteplase/placebo trial) and to assess the effect of immediate percutaneous transluminal coronary angioplasty (PTCA) in addition to alteplase (alteplase/PTCA trial). One-year follow-up results are reported. METHODS AND RESULTS: In the alteplase/placebo trial, 721 patients with chest pain of less than 5 hours and extensive ST-segment elevation were allocated at random to 100 mg alteplase or placebo (double-blind) over 3 hours. In the alteplase/PTCA trial, 367 similar patients received alteplase and subsequently were allocated at random to immediate coronary angiography and angioplasty of the infarct-related vessel or control. All patients received aspirin and intravenous heparin. In the alteplase/placebo trial, mortality during the first year was reduced by 36% with alteplase (from 9.3% to 5.6%; difference, -3.7%; 95% confidence interval, -7.5% to 0.2%). Revascularization was performed more frequently after alteplase, and more patients in the alteplase group were in New York Heart Association functional class I or II. Reinfarction tended to occur more frequently after alteplase than after placebo. In the alteplase/PTCA trial, reinfarction was less common after immediate PTCA, and revascularization procedures were less frequent. However, this benefit was offset by a high rate of immediate reocclusion and early recurrent ischemia and by higher mortality at 1 year (9.3% versus 5.4%; difference, 3.9%; 95% confidence interval, -1.5% to 9.2%) in the invasive group. In a multivariate analysis of 1,043 hospital survivors, mortality after discharge was related to coronary anatomy, left ventricular function, age, and previous infarction but not to initial treatment allocation. Reinfarction after hospital discharge tended to be more common after alteplase and related to coronary anatomy. CONCLUSIONS: Benefit from treatment with alteplase, heparin, and aspirin is not diminished at 1 year. Routine immediate PTCA does not confer additional benefit. Prognosis after hospital discharge mainly is determined by coronary anatomy and residual left ventricular function and is unrelated to initial treatment assignment.
Angioplasty, Balloon, Coronary↗
Seizures and fever: can we rule out meningitis on clinical grounds alone?
A study was done of 309 children seen in two ERs with a first seizure and fever to assess whether meningitis could be recognized using readily available clinical information. Among these children, 23 (7%) cases of meningitis were diagnosed. A group of 69 children with seizures and fever but no meningitis served as controls. Signs from ER examinations that discriminated between children with and those without meningitis were: petechiae, nuchal rigidity, coma, persistent drowsiness, ongoing convulsions, and paresis or paralysis; 21 cases were thus identified. Two children with a suspicious history but none of these signs proved to have meningitis. Children whose seizures showed no complex features and whose febrile illness revealed no suspicious features did not have meningitis. Our results indicate that based on available clinical data, meningitis can be ruled out in children presenting with seizures and fever; thus, there is no need for routine investigation of cerebrospinal fluid.
Blood Sedimentation↗
Reasons for the lack of benefit of immediate angioplasty during recombinant tissue plasminogen activator therapy for acute myocardial infarction: a regional wall motion analysis. European Cooperative Study Group.
Regional ventricular wall motion analysis utilizing three different methods was performed on predischarge left ventriculograms from 291 of 367 patients enrolled in a randomized trial of single chain recombinant tissue-type plasminogen activator (rt-PA), aspirin and heparin with and without immediate angioplasty in patients with acute myocardial infarction. With univariate analysis, no difference in regional wall motion variables between the two treatment groups was observed. However, with individual baseline risk assessment by multivariate linear regression analysis using baseline characteristics known to be related to left ventricular function after thrombolytic therapy or outcome of coronary angioplasty, or both, an excess of high risk patients in the invasive treatment group was detected. To adjust for this unequal distribution of baseline risk, multivariate linear regression analysis was performed. No benefit of immediate coronary angioplasty was observed after adjustment. Reocclusion or reinfarction, or both, occurred more frequently in the invasive than in the noninvasive treatment group (18% versus 13%, respectively). Among patients with a patent infarct-related vessel on angiography between days 10 and 22 and without reinfarction before angiography, there was a trend toward benefit from the invasive strategy, indicating that reocclusion and reinfarction might be responsible for the lack of benefit of the invasive strategy. This implies that immediate coronary angioplasty may be beneficial in selected patients, provided that these complications can be prevented.
Angioplasty, Balloon, Coronary↗
The effects of nisoldipine on the total ischaemic burden: the results of the ROCKET study.
This study was designed to examine the effects of nisoldipine (relative to placebo), a new dihydropyridine calcium entry blocking agent, in the treatment of silent ischaemia in conventional doses. A total of 409 patients with proven coronary artery disease were screened and of this 64 had at least six episodes or a total duration of 30 min of ST segment depression (1 mm lasting at least 1 min) over 48 h. Fifty-two patients ultimately completed a randomized double-blind cross-over study comparing nisoldipine 5 mg twice a day, nisoldipine 10 mg daily and placebo. There was a reduction in the ST segment integral and number of episodes of ST segment depression when compared to placebo on treatment with nisoldipine 5 mg twice a day and nisoldipine 10 mg daily. However, the confidence limits were wide and crossed the no-treatment effect line. In addition, the nisoldipine doses neither affected the circadian distribution of ischaemic episodes nor caused an alteration of the workload achieved either at peak exercise or at 1 mm ST segment depression measured 24 h after nisoldipine 10 mg or 12 h after nisoldipine 5 mg. We conclude that frequent silent ischaemia in patients with proven coronary artery disease is relatively uncommon; it accounts for approximately 16% of patients with positive exercise. In these patients nisoldipine, given as 5 mg twice a day and 10 mg daily, showed no significant therapeutic effects, either on the frequency or severity of silent ischaemia. New formulations of slow release nisoldipine are consequently being developed so that a fuller 24 h therapeutic profile may be obtained.
Coronary Disease↗
QTc prolongation measured by standard 12-lead electrocardiography is an independent risk factor for sudden death due to cardiac arrest.
BACKGROUND: QTc prolongation has been implicated as a risk factor for sudden death; however, a controversy exists over its significance. METHODS AND RESULTS: In the Rotterdam QT Project, 6,693 consecutive patients who underwent 24-hour ambulatory electrocardiography were followed up for 2 years; of these, 245 patients died suddenly. A standard 12-lead electrocardiogram and clinical data at the time of 24-hour ambulatory electrocardiography were collected for all patients who died suddenly and for a random sample of 467 patients from the study cohort. In all patients without an intraventricular conduction defect (176 patients who died suddenly and 390 patients from the sample), QT interval duration was measured in leads I, II, and III and corrected for heart rate with Bazett's formula (QTc). In patients without evidence of cardiac dysfunction (history of symptoms of pump failure or an ejection fraction less than 40%), QTc of more than 440 msec was associated with a 2.3 times higher risk for sudden death compared with a QTc of 440 msec or less (95% confidence interval: 1.4, 3.9). In contrast, in patients with evidence of cardiac dysfunction, the relative risk of QTc prolongation was 1.0 (0.5, 1.9). Adjustment for age, gender, history of myocardial infarction, heart rate, and the use of drugs did not alter these relative risks. CONCLUSIONS: These data indicate that in patients without intraventricular conduction defects and cardiac dysfunction, QTc prolongation measured from the standard electrocardiogram is a risk factor for sudden death independent of age, history of myocardial infarction, heart rate, and drug use. In patients with cardiac dysfunction, QTc duration is not related to the risk for sudden death.
Death, Sudden↗
Quantitative coronary angiography to measure progression and regression of coronary atherosclerosis. Value, limitations, and implications for clinical trials.
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Clinical Trials as Topic↗
Primary prevention in hypertension. Valid conclusions from observational studies.
Relatively few observational (i.e., nonexperimental) studies have been conducted to examine the role of antihypertensive drug therapy in the primary prevention of coronary heart disease. To draw valid conclusions from experimental or observational studies, internal validity should be ensured. In particular, similarity of "extraneous" effects, of information, and of prognosis between the treatment groups compared in a particular study is needed. Because allocation of participants to antihypertensive drug therapy in observational studies is nonrandomized by definition, special efforts should be made to achieve comparability of prognosis, that is, to avoid "confounding by indication." Follow-up and case-control studies, the two main types of observational studies, also offer certain advantages over randomized clinical trials, particularly when different classes of drugs are compared. Although few valid observational studies on the efficacy of drug therapy for hypertension in the primary prevention of first coronary events have been published, the available data suggest that beta-blockers might confer greater protection than other drug regimens. However, more evidence is needed to confirm these findings. It is concluded that observational studies could play an increasing role in the assessment of the role of antihypertensive therapy in the primary prevention of coronary heart disease when the inherent potentials and pitfalls of these studies are appreciated.
Adrenergic beta-Antagonists↗