de Pieter Graeff

Accelerated decline and prognostic impact of renal function after myocardial infarction and the benefits of ACE inhibition : the CATS randomized trial

AIMS Information regarding the cardiorenal axis in patients after a myocardial infarction (MI) is limited. We examined the change in renal function after a first MI, the protective effect of angiotensin converting enzyme (ACE) inhibition and the prognostic value of baseline renal function. METHODS AND RESULTS The study population consisted of 298 patients with a first anterior wall MI who were randomized to the ACE inhibitor captopril or placebo after completion of streptokinase infusion. Renal function, by means of glomerular filtration rate (GFR), was calculated using the Cockroft-Gault equation (GFR(c)). In the placebo group, renal function (GFR(c)) declined by 5.5 min(-1)within 1 year, vs only 0.5 ml min(-1)in the ACE inhibitor group (P<0.05). This beneficial effect of captopril was most pronounced in patients with the most compromised renal function at baseline. The incidence of chronic heart failure (CHF) within 1 year increased significantly with decreasing GFR(c)(divided into tertiles: 24.0, 28.9, and 41.2%; P<0.01). The risk-ratio for GFR(c)<81 ml min(-1)vs >103 mL min(-1)was 1.86 (95% CI 1.11-3.13; P=0.019). CONCLUSIONS Renal function markedly deteriorates after a first MI, but is significantly preserved by ACE inhibition. Furthermore, an impaired baseline renal function adds to the prognostic risk of developing CHF in patients after a first anterior MI.

Impact of Safety-Related Regulatory Action on Clinical Practice A Systematic Review

AbstractBackground: After market approval, new serious safety issues are regularly identified for drugs that lead to regulatory action to inform healthcare professionals. However, the effectiveness of these safety-related regulatory actions is under question. We currently lack a comprehensive overview of the effects of these drug safety warnings on clinical practice to resolve the debate about their effectiveness. Objective: The aim of this systematic review is to provide an overview of studies that assessed the impact of safety warnings. Study Selection: A systematic search was performed for articles assessing the impact of Direct Healthcare Professional Communications or ‘Dear Doctor’ letters, Black Box Warnings and Public Health Advisories on clinical behaviour published between January 1996 and January 2010. The following variables were extracted: publication year, country, name of the drug, safety issue, specific safety warning (Direct Healthcare Professional Communication/Black Box Warning/Public Health Advisory), effect (intended/unintended) of the safety warning, outcome measure and study design. Papers were checked for several quality aspects. Study data were summarized using descriptive analyses. Results: A total of 50 articles were identified. Two articles assessed two different drugs and were therefore counted twice (n = 52). Thirty-three articles described the impact of safety warnings issued for three drugs and drug groups, i.e. third-generation oral contraceptives, cisapride and selective serotonin reuptake inhibitors. The remaining 19 articles described a broad variety of 14 drugs and drug groups. Twenty-five studies applied an interrupted time series design, 23 a controlled or uncontrolled before/after design, and four articles applied both. None of the articles could rule out the influence of confounding factors. The intended effects were reported in 18 (72%) of the 25 before/after analyses, whereas only 11 (41%) of the 27 interrupted time series analyses reported an impact. Only two (8%) of the before/after analyses against 11 (41%) of the interrupted time series analyses reported mixed impacts. When unintended effects were assessed in case of selective serotonin reuptake inhibitors and third-generation oral contraceptives, these were almost always present: in 19 of 22 and 4 of 5 articles, respectively. Our review shows that safety-related regulatory action can have some impact on clinical practice but firm conclusions are difficult to draw. Evidence is primarily based on three drugs and drug groups. Almost half of the studies had inadequate before/after designs and the heterogeneity in analyses and outcome measures hampered the reporting of overall effect sizes. Studies with adequate interrupted time series design reported a more mixed impact of safety warnings than before/after studies. Furthermore, this review shows the relevance of considering not only the intended but also the unintended effects of safety warnings. Conclusions: There is a clear need for further research with appropriate study designs and statistical analyses, with more attention to confounding factors such as media coverage, to understand the impact of safety-related regulatory action.

High Prevalence of Concentric Remodeling in Elderly Individuals With Isolated Systolic Hypertension From a Population Survey

Echocardiographic determination of left ventricular mass index (LVMI) is shown to be valuable in the assessment of cardiovascular risk. Determination of left ventricular geometry, including concentric remodeling, provides additional prognostic information. In isolated systolic hypertension (ISH), the few echocardiographic studies available show an increased LVMI, but criteria and patient populations differ. No comparison with diastolic hypertension (DH) has been made, nor has left ventricular geometry (with concentric remodeling) been evaluated. We compared both LVMI and left ventricular geometry of newly diagnosed ISH subjects with normotensive and DH subjects, all previously untreated and from the same population. The echocardiographic LVMI of 97 previously untreated ISH subjects (4 x systolic pressure > or = 160 mm Hg, diastolic pressure < 95 mm Hg) was clearly elevated compared with values in age- and sex-matched normotensive subjects (98 and 71 g/m2, respectively; P < .001). The geometric pattern was abnormal in most ISH subjects, with a high prevalence (43%) of concentric remodeling. Both LVMI and left ventricular geometry of ISH subjects did not differ significantly from values in DH subjects (LVMI, 92 g/m2; concentric remodeling, 56%). Sex differences in LV geometry in ISH were present only with the Framingham criteria, not with the Koren criteria. This study shows a high prevalence of concentric remodeling in elderly individuals with previously untreated ISH. The increase of LVMI and abnormality in left ventricular geometry are comparable with those in DH subjects, further defining the place of ISH as a cardiovascular risk factor in the elderly. Whether there are sex differences in cardiac adaptation in ISH and whether the geometric classification can be used to adjust treatment remain to be investigated.

Impact of Safety-Related Regulatory Action on Drug Use in Ambulatory Care in the Netherlands

The effect of Direct Healthcare Professional Communications (DHPCs) informing health‐care providers of serious drug safety issues has been questioned. The aim of this study was to evaluate the impact of DHPCs on drug use. Nationwide dispensing data for the period 2000–2008 for new users of 46 drugs with one or more DHPCs were assessed. Impact on short‐term volume of use was evaluated with regression models, and the presence of long‐term changes in use was evaluated with interrupted time series analyses incorporating preexisting trends. The short‐term prescription level was lower post‐DHPC in 28 (48.3%) of 58 cases. Twenty (34.5%) DHPCs resulted in long‐term changes in use. A long‐term mean reduction in use was observed in 26.7% of cases (95% confidence interval, −15.2 to −38.2%). Long‐term changes in use were not significantly related to preexisting trends in use. Although short‐ and long‐term decreases in use were observed after only half and a third of DHPCs, respectively, the decrease was substantial.

Microalbuminuria is Related to Marked End Organ Damage in Previously Untreated, Elderly Hypertensive Patients

We wondered whether, in an elderly hypertensive population in a primary prevention setting, free from diabetes mellitus and clinical atherosclerosis, differences between end organ damage and microalbuminuria (MA) could be found using a lower level of urinary albumin excretion than that of classically defined MA. From a population survey of 173 previously untreated hypertensive patients (4 2 blood pressure systolic S 160 and h 220 mmHg, and/or diastolic S 95 and h 115 mmHg), mean age 67 - 4 years, were screened for MA (defined as albumin excretion between 20 and 300 mg/24 h). End organ damage was determined by B-mode ultrasound scanning echocardiography. Out of 173 hypertensives, 14 showed MA (8%). These hypertensives had a significantly higher intima media thickness (IMT; 1.01 - 0.21 vs 0.88 - 0.6 mm, p < 0.05) and increased left ventricular mass index (118 - 31 vs 103 - 22 g/m 2 , p < 0.05) than hypertensives without MA. Linear regression analysis showed that MA, age, male gender and diastolic blood pressure were independently related to IMT, while systolic blood pressure, male gender and body mass index were independently related to left ventricular mass. Even using lower levels of urinary albumin excretion rate, patients with MA had significantly higher IMT and increased left ventricular mass. Moreover, MA was independently related to IMT in these elderly hypertensives. These results suggest that the threshold value for MA should be reconsidered in hypertension.

Effects of nifedipine on carotid and femoral arterial wall thickness in previously untreated hypertensive patients

Background: Experimental and clinical evidence suggests that calcium-channel blockers may retard the atherosclerotic process after long-term treatment. Whether these effects exist after intermediate-term treatment in hypertensive patients is mainly unknown. Objective: To determine the 26-week effects of the long-acting calcium-channel blocker nifedipine on intima media thickness (IMT) in newly found hypertensive patients. Design: Open-label study with blinded end-point analysis. Methods: From a population survey, 131 previously untreated mild hypertensives (4× systolic blood pressure between 160 and 220 mmHg and/or diastolic blood pressure between 95 and 115 mmHg) were included. Patients were treated with long-acting nifedipine 30-60 mg targeted to reach a predetermined drop in blood pressure. Prior to and after 26 weeks of treatment, IMT was measured by ultrasonography in the carotid and femoral artery. The combined mean maximal far wall IMT was used as primary endpoint. Change from baseline was evaluated by paired t-test in an intention-to-treat analysis. Results: The mean maximal far wall IMT at baseline was 1.03 ± 0.23 mm, and decreased by 0.078 mm (95% confidence interval, CI 0.044-0.111) after treatment. Regression analysis, including baseline IMT and changes of blood pressure, showed that reduction of IMT was mostly influenced by baseline IMT (p < 0.001; model R [Formula: See Text] = 0.11). Conclusion: Our observations show that 26 weeks of nifedipine treatment inhibits IMT progression in these newly found hypertensive patients. This effect was mostly seen in arterial walls with highest IMT before treatment, suggesting that patients with highest cardiovascular risk benefit most of antihypertensive treatment.

CONNECTING PRE-MARKETING CLINICAL RESEARCH AND MEDICAL PRACTICE Opinion-based Study of Core Issues and Possible Changes in Drug Regulation

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Effects of diltiazem on reperfusion-induced arrhythmias in vitro and in vivo

The effects of the calcium antagonist, diltiazem, on myocardial injury during ischemia and reperfusion were studied both in vitro, in the isolated rat heart, and in vivo, in a closed-chest pig model. In the isolated rat heart, administration of diltiazem before or at the onset of ischemia resulted in a dose-dependent reduction of the incidence and duration of ventricular fibrillation. This reduction was associated with a dose-dependent reduction in overflow of ATP catabolites (adenosine, inosine, hypoxanthine and xanthine). Both changes were significant at concentrations of 3 X 10(-7) M diltiazem and higher. When 3 X 10(-7) M diltiazem was administered upon reperfusion no effect on the incidence of ventricular fibrillation and on ischemia induced total purine overflow was observed. However, the duration of ventricular fibrillation and purine overflow at 5 min after reperfusion were significantly reduced. In the pig experiments all untreated animals (n = 8) showed accelerated idioventricular rhythm (AIVR) upon reperfusion which lasted for 22 +/- 5 min after which sinus rhythm returned. Only two out of five treated animals (450 micrograms/kg/2 h) had an AIVR. Upon reperfusion both groups showed a substantial rise in noradrenaline concentration in the coronary sinus blood, but after 5 min this was significantly less in the treated group. Creatine kinase-kinetics were not altered by diltiazem, but the maximum creatine kinase level was significantly reduced. Within 4 days after the acute experiment 50% of the untreated animals died suddenly, whereas no sudden deaths occurred in the diltiazem group (P less than 0.05). Seven days after the acute experiment, sustained ventricular tachycardia could be induced with programmed electrical stimulation in three out of four surviving untreated pigs. In none of the diltiazem treated pigs was ventricular tachycardia inducible. The results of this study show that the calcium antagonist diltiazem can beneficially influence the events during ischemia and during reperfusion, both in vitro and in vivo; this benefit is associated with a reduction of ATP catabolism, creatine kinase release and noradrenaline overflow. Furthermore, diltiazem reduces electrical instability in the chronic phase of myocardial infarction.

ROLE OF ANGIOTENSIN-CONVERTING ENZYME-INHIBITION IN ANGINA-PECTORIS

Summary: There are various reasons to assume a beneficial effect of angiotensin-converting enzyme (ACE) inhibitors in patients with angina pectoris. Reduction of preload and afterload and a sympatholytic action may diminish myocardial oxygen demand. Local vasodilatory effects on the coronary vasculature may cause a relative increase in myocardial oxygen supply, although this can be nullified by the reduction in coronary perfusion pressure. Despite these potentially beneficial effects, placebo-controlled studies on exercise testing have shown variable results and do not justify the widespread use of these agents in chronic effort-induced angina pectoris. Nevertheless, certain subgroups of anginal patients may be identified in whom further studies are needed, especially patients who have unstable angina pectoris or are in the acute phase of myocardial infarction, patients with left ventricular dysfunction without overt heart failure, and patients with hypertension and left ventricular hypertrophy. Apart from this, ACE inhibitors may potentiate the effects of nitrates and reverse tolerance, especially inhibitors that contain a sulfhydryl group. In additional studies, a low starting dose and a long duration of treatment appear to be essential to optimize tissue penetration in the heart and to minimize negative effects due to the reduction in perfusion pressure.

Comparative trials in registration files of cardiovascular drugs: Comparator drugs and dosing schemes.

Registration files of 13 cardiovascular drugs were analysed with respect to the number of double‐blind phase‐III clinical trials, the use of placebo and active comparator drugs and their dosing schemes. Half of the 146 double‐blind trials used active comparator drugs. The majority of files included first‐choice reference drugs, but we also found trials in three files with lower dosing schemes of comparator drugs and four files which included only placebo or active controlled double‐blind trials. To allow a better interpretation of the information provided in European Public Assessment Reports, which are published for every product approved for marketing in the European Union, uniform reporting is recommended on basic details of trial design, such as comparator drugs used and dosing schemes.