Joachim Schrader

The Pharao study: prevention of hypertension with the angiotensin-converting enzyme inhibitor ramipril in patients with high-normal blood pressure – a prospective, randomized, controlled prevention trial of the German Hypertension League

Background The prevention of hypertension with the angiotensin-converting enzyme inhibitor ramipril in patients with high-normal blood pressure study addresses the issue of whether progression to manifest hypertension in patients with high-normal blood pressure can be prevented with treatment. Methods A total of 1008 participants with high-normal office blood pressure were randomized to ramipril treatment group (n = 505) and a control group (n = 503). The patients were followed up for 3 years. Primary endpoint was to prevent or delay the progression to manifest hypertension. Secondary endpoints were reduction in the incidence of cerebrovascular and cardiovascular events, as well as the development of hypertension as defined by ambulatory blood pressure monitoring. Findings One hundred and fifty-five patients (30.7%) in the ramipril group, and 216 (42.9%) in the control group reached the primary endpoint (relative risk reduction 34.4%, P = 0.0001). Ramipril also proved to be more effective in reducing the incidence of manifest office hypertension in patients with baseline ambulatory blood pressure monitoring high-normal blood pressure. The incidence of cerebrovascular and cardiovascular events showed no statistically significant differences between the two groups. Cough was more frequent in the ramipril group (4.8 vs. 0.4%). Interpretation There is now good clinical evidence that patients with high-normal blood pressure (prehypertension) are more likely to progress to manifest hypertension than patients with optimal or normal blood pressure. Additional ambulatory blood pressure monitoring seems to be essential to achieve correct diagnosis. Treatment of patients with high-normal office blood pressure with the angiotensin-converting enzyme inhibitor was well tolerated, and significantly reduced the risk of progression to manifest hypertension.

Low-grade albuminuria and cardiovascular risk : what is the evidence?

Microalbuminuria (MA), conventionally defined as a urinary albumin excretion (UAE) of 30–300 mg/day, is recognised as a marker of endothelial dysfunction. Furthermore, it represents an established risk factor for cardiovascular morbidity and mortality and for end-stage renal disease in individuals with an adverse cardiovascular risk profile. It is common in the general population, particularly in patients with diabetes mellitus or arterial hypertension. There is growing evidence from prospective observational trials that UAE levels well below the current MA threshold (“lowgrade MA”) are also associated with an increased risk of incident cardiovascular disease and allcause mortality. Even in apparently healthy individuals (without diabetes or hypertension), such an association has been shown. As albuminuria screening assays that are reliable even in the lower ranges are commercially available, there may be an important clinical role for MA in disease screening, comparable to the role of blood pressure and lipid screening. MA is modifiable, and the inhibition of the renin-angiotensin system by ACE inhibitors and AT1 receptor antagonists has been shown to result in a lower incidence of cardiovascular events.

Improvement of hypertension management by structured physician education and feedback system: cluster randomized trial.

Introduction We aimed to assess whether hypertension management with a structured physician information program and a feedback system leads to improved blood pressure (BP) control and cardiovascular outcomes. Methods Cluster randomized (3: 1), open, monitored, multicenter trial in Germany. Primary care-based physicians in the information group (IG) received detailed training on hypertension guidelines, feedback on target-level attainment, and a reminder to intensify treatment after each patient visit, whereas the observation/control group (CG) did not receive any such measures. A three-level mixed model was developed. Time-independent level differences between groups, group-independent changes, and nonparallel group-specific changes over time were tested. Results A total of 15 041 (78.1%) hypertensive patients were in the IG and 4213 (21.9%) in the CG. By 1-year follow-up, 82.9% of patients in the IG and 81.5% in the CG remained in the study. The guideline-oriented BP target was attained by 56.8% in the IG and 52.5% in the CG (+ 4.3%, P = 0.03), whereas the individual BP target was attained by 57.0% in the IG and 51% in the CG (P = NS). BP control in the IG was achieved 2 months earlier on average. Clinical inertia, defined as the absence of medication changes, despite noncontrol of BP, occurred significantly less often in the IG group. One-year cardiovascular outcomes did not differ between groups. Conclusion The delivery of systematic information in connection with a feedback system reduces clinical inertia and improves guideline adherence. Although compared with earlier studies, the hypertension control rates obtained are higher, there is still considerable room for improvement. Eur J Cardiovasc Prev Rehabil 17:271-279

Plasma-Endothelin bei Normalpersonen und Patienten mit nephrologisch-rheumatologischen und kardiovaskulären Erkrankungen

SummaryPlasma concentrations of the recently isolated potent vasoconstrictory peptide endothelin were measured in 382 patients. The investigations were performed by means of a sensitive radioimmunoassay specific for Endothelin-1, 2.The results from 110 healthy volunteers displayed a normal range of 44.67±3.51 pg/ml. Significantly raised levels were found in 33 patients with chronic end-stage renal failure both before and after hemodialysis. In contrast, 35 patients with compensated renal insufficiency did not differ from the normals. Sixty-five patients after kidney transplantation revealed significantly elevated levels, as did 27 patients with acute myocardial infarction, 8 after coronary bypass surgery, and 5 with liver cirrhosis. The mean values of 27 patients with untreated hypertension, 22 with secondary hypertension, of various causes and 16 with coronary artery disease were comparable to the normal population. The values were significantly decreased in 9 pregnant women with hypertension and proteinuria. A marked decline was found in 5 patients with systemic lupus erythematodes, while 20 patients with rheumatoid arthritis demonstrated only a slight decrease.The pathophysiological role of endothelin as a local or circulating hormone in regulating systemic blood pressure or release of other hormones remains to be determined.Plasma concentrations of the recently isolated potent vasoconstrictory peptide endothelin were measured in 382 patients. The investigations were performed by means of a sensitive radioimmunoassay specific for Endothelin-1, 2. The results from 110 healthy volunteers displayed a normal range of 44.67 +/- 3.51 pg/ml. Significantly raised levels were found in 33 patients with chronic end-stage renal failure both before and after hemodialysis. In contrast, 35 patients with compensated renal insufficiency did not differ from the normals. Sixty-five patients after kidney transplantation revealed significantly elevated levels, as did 27 patients with acute myocardial infarction, 8 after coronary bypass surgery, and 5 with liver cirrhosis. The mean values of 27 patients with untreated hypertension, 22 with secondary hypertension, of various causes and 16 with coronary artery disease were comparable to the normal population. The values were significantly decreased in 9 pregnant women with hypertension and proteinuria. A marked decline was found in 5 patients with systemic lupus erythematodes, while 20 patients with rheumatoid arthritis demonstrated only a slight decrease. The pathophysiological role of endothelin as a local or circulating hormone in regulating systemic blood pressure or release of other hormones remains to be determined.

Anwendung von niedermolekularem Heparin bei Hämodialysepatienten

Low-molecular-weight (LMW) heparin has been compared to standard unfractionated (UF) heparin in a total of 49 patients on hemodialysis and hemofiltration in order to determine the necessary therapeutic dose and its effect on the coagulation system. A LMW heparin dose corresponding to 50% of the normal UF heparin dose was found to produce similar plasma heparin levels (anti-FXa-U/ml) in particular on minimal heparinization. At higher doses, UF heparin produced a more marked increase in plasma-heparin than did LMW heparin. Highly significant differences were found between UF and LMW heparin in their effects on PTT and thrombin time. Partial thromboplastin time (PTT) increased under UF heparin by an average of 120 s whereas LMW heparin only produced an increase of 5-7 s. Thrombin time was increased by 250-280 s under UF heparin and by 5-8 s under LMW heparin. With this LMW heparin dose of 50% of the UF heparin dose, no thrombosis of the extracorporal system occurred and no macroscopic detectable thrombotic material was found in the dialyzers or filters. No significant differences were observed between the effects of UF and LMW heparin on Factor VIII activity and fibrin monomers, so that a difference in coagulation activation between the two heparins can be excluded. Furthermore, there were no changes in thromboplastin time according to Quick, fibrinogen, antithrombin III, plasminogen, and a2-antiplasmin.(ABSTRACT TRUNCATED AT 250 WORDS)SummaryLow-molecular-weight (LMW) heparin has been compared to standard unfractionated (UF) heparin in a total of 49 patients on hemodialysis and hemofiltration in order to determine the necessary therapeutic dose and its effect on the coagulation system. A LMW heparin dose corresponding to 50% of the normal UF heparin dose was found to produce similar plasma heparin levels (anti-FXa-U/ml) in particular on minimal heparinization. At higher doses, UF heparin produced a more marked increase in plasma-heparin than did LMW heparin. Highly significant differences were found between UF and LMW heparin in their effects on PTT and thrombin time. Partial thromboplastin time (PTT) increased under UF heparin by an average of 120 s whereas LMW heparin only produced an increase of 5–7 s. Thrombin time was increased by 250–280 s under UF heparin and by 5–8 s under LMW heparin. With this LMW heparin dose of 50% of the UF heparin dose, no thrombosis of the extracorporal system occurred and no macroscopic detectable thrombotic material was found in the dialyzers or filters. No significant differences were observed between the effects of UF and LMW heparin on Factor VIII activity and fibrin monomers, so that a difference in coagulation activation between the two heparins can be excluded. Furthermore, there were no changes in thromboplastin time according to Quick, fibrinogen, antithrombin III, plasminogen, and a2-antiplasmin. Thus effective Anti-FXa levels and by similar antithrombotic activity, LMW heparin will probably present less of a bleeding risk because of its reduced effect on PTT and thrombin time. LMW heparin therefore appears to be a good alternative to UF heparin for patients with renal insufficiency requiring dialysis. LMW heparin is indicated in particular in patients at bleeding risk, with diabetic retinopathy, on therapy with oral anticoagulants or platelet aggregation inhibitors, and with thrombocytopenia.

Fehlender nächtlicher Blutdruckabfall in der 24-Stunden Blutdruckmessung: Hinweis auf eine sekundäre Hypertonie

SummaryNon invasive 24 hours ambulatory blood pressure monitoring was performed in 81 patients with secondary hypertension (renoparenchymatous nephropathyn=15, diabetic nephropathyn=10, Conns diseasen=4, renal artery stenosisn=15, pheochromocytoman=2, hemodialysis patientsn=15 and patients after kidney transplantationn=20). The results were compared to 201 patients with essential hypertension.The results showed that 98.5% of patients with essential hypertension have a nightly decline in blood pressure of at least 15 mmHg (systolic+diastolic), whereas 69% of patients with secondary hypertension showed either an attenuated circadian rhythm or no circadian rhythm. Patients with pheochromocytoma who had a night time increase in blood pressure demonstrated the greatest difference to the essential hypertension collective followed by patients with diabetic nephropathy, Conns disease and the group of patients after kidney transplantation. After successful treatment of the condition leading to hypertension circadian periodicity returned in some patients.In summary these results suggest that the absence of a night time decline in blood pressure during 24-hour-ambulatory monitoring is an indication of secondary hypertension.Non invasive 24 hours ambulatory blood pressure monitoring was performed in 81 patients with secondary hypertension (renoparenchymatous nephropathy n = 15, diabetic nephropathy n = 10, Conns disease n = 4, renal artery stenosis n = 15, pheochromocytoma n = 2, hemodialysis patients n = 15 and patients after kidney transplantation n = 20). The results were compared to 201 patients with essential hypertension. The results showed that 98.5% of patients with essential hypertension have a nightly decline in blood pressure of at least 15 mmHg (systolic + diastolic), whereas 69% of patients with secondary hypertension showed either an attenuated circadian rhythm or no circadian rhythm. Patients with pheochromocytoma who had a night time increase in blood pressure demonstrated the greatest difference to the essential hypertension collective followed by patients with diabetic nephropathy, Conns disease and the group of patients after kidney transplantation. After successful treatment of the condition leading to hypertension circadian periodicity returned in some patients. In summary these results suggest that the absence of a night time decline in blood pressure during 24-hour-ambulatory monitoring is an indication of secondary hypertension.

24-Stunden-Blutdruckmessungen im Verlauf der normalen Schwangerschaft und bei hypertensiven Schwangeren

SummaryNoninvasive 24-hour ambulatory blood pressure monitoring was performed in 17 normotensive and 19 preeclamptic pregnant women. The normotensive women showed a significant nightly decline in their systolic and diastolic blood pressure. In contrast, the preeclamptic women demonstrated either an attenuated circadian rhythm or no circadian rhythm at all. This result was even more pronounced in patients with severe hypertension, some of whom had a nocturnal increase in blood pressure in spite of being treated with antihypertensive drugs in an evening dose. The lack of nocturnal blood pressure decrease was also found 24 hours post partum.In summary, these results suggest that preeclamptic women are endangered by hypertensive emergencies mostly during the night. Therefore blood pressure controls should be extended into the night, and antihypertensive drugs should also be given in a sufficient evening dose.Noninvasive 24-hour ambulatory blood pressure monitoring was performed in 17 normotensive and 19 preeclamptic pregnant women. The normotensive women showed a significant nightly decline in their systolic and diastolic blood pressure. In contrast, the preeclamptic women demonstrated either an attenuated circadian rhythm or no circadian rhythm at all. This result was even more pronounced in patients with severe hypertension, some of whom had a nocturnal increase in blood pressure in spite of being treated with antihypertensive drugs in an evening dose. The lack of nocturnal blood pressure decrease was also found 24 hours post partum. In summary, these results suggest that preeclamptic women are endangered by hypertensive emergencies mostly during the night. Therefore blood pressure controls should be extended into the night, and antihypertensive drugs should also be given in a sufficient evening dose.

Parameters of the Kallikrein-Kinin, Coagulation and Fibrinolytic Systems as Early Indicators of Kidney Transplant Rejection

In order to find early indicators of kidney transplant rejection before clinical symptoms were noticed, parameters of the coagulation, fibrinolytic and kallikrein-kinin systems were measured. Nineteen patients were followed before and daily after kidney transplantation during the first week and every second day in the following weeks. All patients received immunosuppressive therapy with cyclosporin and corticoids. Ten patients suffered from transplant rejection. The first rejection occurred on the 7th day after transplantation. Of all the parameters measured, kallikrein inhibition, beta-FXIIa inhibition, plasminogen and antithrombin III were early indicators of kidney transplant rejections. A rise in these parameters could be demonstrated 2-3 days before clinical signs were noticed. In the other 9 patients no significant rises in antithrombin III, plasminogen, kallikrein inhibition and beta-FXIIa inhibition could be found.

Long-Term Intraperitoneal Application of Low Molecular Weight Heparin in a Continuous Ambulatory Peritoneal Dialysis Patient with Deep Vein Thrombosis

J. Schrader, MD, Department of Nephrology, University Hospital, Robert-Koch-Strasse 40, D-3400 Göttingen (FRG) Dear Sir, We read with interest the recent report of Ponce et al. [1] in this journal on the interference of heparin with peritoneal solute transport. It has shown that intraperitoneal application of standard heparin does not affect or only slightly affects systemic blood coagulation [1–3]. There are, however, no reports dealing with the intraperitoneal use of low molecular weight (LMW) heparin in peritoneal dialysis patients. Several studies have demonstrated that LMW heparin has a powerful antithrombotic effect and high antifactor Xa activity with only a minimal anticoagulant activity as reflected by partial thromboplastin time (PTT) and thrombin time [4–6]. LMW heparin is also a good alternative in hemodialysis and has several advantages over standard heparin [7,8]. We have now been able to demonstrate the systemic effect of intraperitoneally applied LMW heparin Kabi 2165 (Fa. Kabi Vitrum, Sweden) in a 63-years-old male continuous ambulatory peritoneal dialysis (CAPD) patient with deep vein thrombosis of the right thigh and lower leg. Because of the patient’s poor vein condition, the necessary anticoagulant therapy was performed exclusively by intraperitoneal use of LMW heparin. A dose of 8,000 antifactor Xa units/2-liter dialysate bag was given 4 times/day. On the first day, a plasma heparin activity of 0.3 antifactor Xa units/ml was found (measured with the chromogenic substrate S-2222). The therapy was continued with this dose, and a heparin level between 0.5 and 0.8 antifactor Xa units/ml was found during the following 3 months (fig. 1), which in our experience constitutes the therapeutic range. In the 4th and 5th months, the heparin activity rose to 1.15 and 1.35 U/ml, respectively. Therefore the dose was reduced to 6,000 antifactor Xa units/bag, and the heparin activity decreased to 0.82 U/ml (fig. 1). The PTT values had

Vaskuläre Demenz und Hypertonie

Dementia and associated diseases will have increasing impact on economical and social system in most countries. As long as no causal therapy for dementia exists, primary prevention, diagnosis and control of risk factors for dementia are crucial. Uncontrolled hypertension is one of the most important risk factors for vascular dementia. An early antihypertensive treatment may reduce cognitive impairment or at least prolong the time to onset of dementia.