Ari Mosenkis

Mechanisms of Hypertension Associated With BAY 43-9006

PURPOSE BAY 43-9006 (sorafenib) is an inhibitor of Raf kinase, the vascular endothelial growth factor (VEGF) receptor-2, and angiogenesis in tumor xenografts. The current study investigated the incidence, severity, and mechanism of blood pressure (BP) elevation in patients treated with BAY 43-9006. PATIENTS AND METHODS Twenty patients received BAY 43-9006 400 mg orally twice daily. BP and heart rate were measured at baseline and then every 3 weeks for 18 weeks. VEGF, catecholamines, endothelin I, urotensin II, renin, and aldosterone were measured at baseline and after 3 weeks of therapy. We assessed vascular stiffness at baseline, after 3 to 6 weeks of therapy, and again after 9 to 10 months of therapy. RESULTS Fifteen (75%) of 20 patients experienced an increase of > or = 10 mmHg in systolic BP (SBP), and 12 (60%) of 20 patients experienced an increase of > or = 20 mmHg in SBP compared with their baseline value, with a mean change of 20.6 mmHg (P < .0001) after 3 weeks of therapy. There were no statistically significant changes in humoral factors, although there was a statistically significant inverse relationship between decreases in catecholamines and increases in SBP, suggesting a secondary response to BP elevation. Measures of vascular stiffness increased significantly during the period of observation. CONCLUSION Treatment with BAY 43-9006 is associated with a significant and sustained increase in BP. The lack of significant change in circulating factors suggests that these humoral factors had little role in the increase in BP.

Pharmacologic adjuvants to epoetin in the treatment of anemia in patients on hemodialysis

Anemia is a common complication of chronic kidney disease, particularly in patients who are on dialysis. The use of recombinant human erythropoietin has led to the eradication of severe anemia in the dialysis population. Correction of anemia in these patients has been associated with better quality of life and clinical outcomes. Some hemodialysis patients have anemia that either is relatively refractory to epoetin therapy or requires very high doses of epoetin (i.e., hyporesponsiveness), despite having adequate iron stores, and are thus unable to achieve or maintain target hemoglobin levels. Several pharmacologic agents have been studied for effects on improving response to epoetin, either to counter hyporesponsiveness or simply to reduce epoetin use for purely economic reasons. This review examines the available literature regarding the efficacy of these potential pharmacologic adjuvants to epoetin in the treatment of anemia in patients on maintenance hemodialysis, with special emphasis on androgens, vitamin C (ascorbic acid), and l‐carnitine. A review of published guidelines and recommendations for use of these agents in hemodialysis patients is provided.

Renal impairment, hypertension and plasma urotensin II

BACKGROUND Human urotensin II (UII) is a potent mammalian vasoconstrictor thought to be produced and cleared by the kidneys. Conflicting data exist regarding the relationship between UII concentrations, kidney function and blood pressure (BP). We measured the associations between kidney function [including end-stage renal disease (ESRD)] and levels of BP with plasma concentrations of UII. METHODS Ninety-one subjects were enrolled. Thirty-one subjects had ESRD (undergoing haemodialysis), 30 subjects had chronic kidney disease (CKD) and 30 control subjects had no kidney disease. Plasma UII concentrations were measured by radioimmunoassay. RESULTS Mean plasma UII concentrations were highest in controls, lower in subjects with ESRD and lowest in subjects with non-ESRD CKD (P<0.0001). UII concentrations correlated negatively with serum creatinine (P=0.0012) and CKD stage, and positively with creatinine clearance (P=0.013). In ESRD subjects, plasma UII (P=0.008) increased after dialysis, while SBP (P=0.007), DBP (P=0.009), serum creatinine (P<0.0001) and serum urea nitrogen (P<0.0001) decreased. UII concentrations were lower in patients with a history of hypertension (HTN) (P=0.016). Age, race and gender did not appear to be associated with UII concentration. However, the distribution of African American race and male gender appear to be associated with increasing stages of chronic kidney disease. CONCLUSIONS These data suggest a potential vasodilatory role of UII in humans with kidney disease or hypertension. The reduction in UII levels in CKD also suggests either reduced production or greater clearance, or both, of UII.

Muscle Cramps and Diuretic Therapy

VOL. 7 NO. 2 FEBRUARY 2005 134 Muscle cramps, notably nocturnal leg cramps, are common symptoms experienced by general medical patients, particularly the elderly.1 Their etiology is varied; most commonly, these cramps are idiopathic. With the notable (and relatively rare) exceptions of serious electrolyte imbalances including hypokalemia, hypomagnesemia and hypocalcemia, these cramps are typically benign in nature. Nevertheless, they can be bothersome. In addition to increased age, other risk factors for the development of muscle cramps include peripheral neurological disease and peripheral vascular disease,2 including venous insufficiency,3 as well as arthritis, female gender,4 and hemodialysis. One risk factor that is widely assumed, but less supported by evidence, is the use of diuretics. Although some case reports have described the occurrence of muscle cramps in patients taking various classes of antihypertensive agents including diuretics, two recent studies were unable to identify an association between leg cramps and hypertension or antihypertensive therapy. The first such study was a retrospective chart review of 50 patients who had been prescribed quinine to treat cramps, compared with 50 age-matched controls.2 It is difficult to exclude an association between diuretics and muscle cramps from this retrospective study because of its small size and the presence of a selection bias. Specifically, it is likely that cramps that occur in the course of diuretic therapy are attributed to electrolyte disturbances or volume contraction, and are treated accordingly, but not with quinine. The second recent study to challenge the notion that diuretics are a common cause of muscle cramps was a cross-sectional survey of 365 general medical patients.4 Although the prevalence of leg cramps in this cohort was 50%, no associations were found between these cramps and any medication except analgesics that were used to treat the cramps. Nevertheless, a review of the Physicians’ Desk Reference database (available at www.pdr.net) suggests a consistent association between diuretics and muscle cramps. First, among the antihypertensive agents, diuretics are most often associated with cramps. In fact, the Physicians’ Desk Reference lists “muscle cramps or spasms” as an adverse effect with an incidence of ≥5% for indapamide, a thiazide-like indoline diuretic. Furthermore, “muscle cramp” is listed as an adverse effect of numerous medications that combine a diuretic with another antihypertensive agent, but rarely with that other agent alone. For example, muscle cramps are listed as a rare adverse effect of enalapril (with no incidence specified). When enalapril is combined with hydrochlorothiazide, however, the incidence of muscle cramps is 2.7%. The mechanism of diuretic-associated cramping (if such an entity truly exists) is likely related to hypokalemia, hypomagnesemia, or volume contraction (with or without metabolic alkalosis). Hypocalcemia is a possible cause during therapy with loop-diuretics such as furosemide, but is unlikely with the hypocalciuric thiazide-type diuretics. Interestingly, potassium-sparing diuretics, such as amiloride, are also associated with cramping. Thus volume contraction appears to be the one mechanism that is common to all classes of diuretics. From the Hypertension Program, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA Address for correspondence: Raymond R. Townsend, MD, University of Pennsylvania, 201 White Building, 3600 Spruce Street, Philadelphia, PA 19104 C o m m o n Q u e s t i o n s a n d A n s w e r s i n t h e M a n a g e m e n t o f H y p e r t e n s i o n

Use of Low Molecular Weight Heparins and Glycoprotein IIb/IIIa Inhibitors in Patients with Chronic Kidney Disease

Despite aggressive intervention, cardiac causes of death, including acute coronary syndrome (ACS), continue to be a major source of mortality in patients with chronic kidney disease (CKD), including end‐stage renal disease (ESRD). Multiple large prospective trials have demonstrated the clinical benefits of both low molecular weight heparin (LMWH) and glycoprotein (Gp) IIb/IIIa inhibitors in treating patients with ACS. Unfortunately patients with significant impairment of kidney function have generally been excluded from these major clinical trials. Consequently relatively little is known about the pharmacokinetics, appropriate dosing, efficacy, and safety of these medications in patients with CKD of various stages. This article examines the available literature regarding the pharmacokinetics, dosing, efficacy, and safety of LMWH and Gp IIb/IIIa inhibitors in patients with CKD.

Sitting on the Evidence: What Is the Proper Patient Position for the Office Measurement of Blood Pressure?

THE JOURNAL OF CLINICAL HYPERTENSION 365 The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7)—as well as earlier reports—states that the proper position for the measurement of blood pressure (BP) is sitting.1 Two questions come to mind regarding this recommendation: Are there significant differences between BPs obtained in the supine and sitting positions? and What is the evidence that BP should be measured in the seated position? There are conflicting data regarding the relationship between supine and sitting BPs in otherwise healthy (i.e., not hypovolemic) individuals. Although both the International Society of Hypertension of the World Health Organization2 and the Hypertension Task Force of the American Heart Association3 assert that the two approaches to BP measurement are equivalent (assuming all measurements are performed with the arm at the level of the right atrium), numerous prospective studies have challenged this notion. Whereas some authors have demonstrated that systolic BP is lower and diastolic BP higher in the sitting, compared with the supine position,4 others have shown that both the systolic and diastolic BP are lower in the sitting position.5,6 Conversely, another group has demonstrated that mean intra-arterial ambulatory systolic and diastolic BP were higher in the sitting position.7 It is noteworthy that the differences in BPs recorded in these studies were as high as 10 mm Hg. Some of the discrepancies between these studies can be explained by differences in technique (i.e., sphygmomanometric vs. oscillometric vs. intra-arterial) and research subject characteristics (i.e., hypertensive or diabetic status). Nevertheless, it is unclear if there is a consistent relationship between these two methods of BP measurement. Furthermore, it is unclear which method better approximates intra-aortic pressure and would thus be a better predictor of cardiovascular outcomes. The strongest argument in favor of routinely measuring BP in the sitting position is that the overwhelming majority of data associating hypertension with poor cardiovascular outcomes and the treatment of hypertension with improved outcomes were derived from studies in which the BP was measured, by protocol, in the sitting position. Specifically, the Framingham study measured BPs in the sitting position.8 Furthermore, the large BP treatment trials of the 1960s and 1970s, namely the Veteran’s Affairs Cooperative Study Group on Antihypertensive Agents9 and the trial of the Medical Research Council (MRC) Working Party on Mild to Moderate Hypertension10 both measured BPs, by protocol, in the sitting position. In addition, two large trials from the late 1980s and early 1990s, the Multiple Risk Factor Intervention Trial (MRFIT)11 and the Systolic Hypertension in From the Department of Medicine, Hypertension Program, University of Pennsylvania School of Medicine, Philadelphia, PA Address for correspondence: Raymond R. Townsend, MD, Department of Medicine, Hypertension Program, University of Pennsylvania School of Medicine, White Building, 3400 Spruce Street, Philadelphia, PA 19104 C o m m o n Q u e s t i o n s a n d A n s w e r s i n t h e M a n a g e m e n t o f H y p e r t e n s i o n

Diastolic Blood Pressure Control: How Low Is Too Low?

THE JOURNAL OF CLINICAL HYPERTENSION 351 It is well established that controlling hypertension through the use of antihypertensive agents reduces morbidity and mortality. It has been further demonstrated that lowering systolic blood pressure (SBP) as well diastolic blood pressure (DBP) confers benefit.1 In the late 1970s, reexamination of Framingham data revealed that whereas there is no level of SBP lowering that does not incrementally improve outcomes, such may not be the case for DBP.2 Subsequently, numerous analyses have been performed demonstrating the J-shaped curve, with increased mortality and coronary events in the groups of subjects whose DBPs were lowered below 65–85 mm Hg.3–5 Many of these analyses were, however, based on small numbers of cases. Three explanations have been offered to explain this phenomenon. One is that diastolic hypotension is frequently noted in conditions such as cardiomyopathy or malignancy and that some of the patients who exhibited this phenomenon may just have been sicker. Another explanation is that low DBP is really a marker for widened pulse pressure, which is an indicator of increased arterial stiffness and atherosclerosis. Finally, some have suggested that diastolic hypotension reduces coronary filling pressures, thereby inducing endocardial ischemia. In practice, isolated diastolic hypotension is a relatively uncommon complication of antihypertensive therapy. On the contrary, many patients are inadequately treated and have both SBP and DBP above the recommended targets. One group where diastolic hypotension may complicate therapy is the elderly. In elderly persons, a common variant of hypertension is isolated systolic hypertension with a wide pulse pressure and normal or even low diastolic pressure. Although numerous studies, notably the Systolic Hypertension in the Elderly Program (SHEP), have demonstrated the considerable benefits of treating this form of hypertension, DBP lowering is an inevitable consequence of such treatment. This reality raises some important questions: At what point in the treatment of isolated systolic hypertension does the potential harm of low DBP outweigh the benefit of lowering SBP? Is the increased event rate associated with diastolic hypotension a result of treatment, or is it seen even in those patients treated with placebo? To address these issues, Somes and colleagues6 reanalyzed the data from the SHEP trial. They found a higher incidence of cardiovascular disease events in those patients with isolated systolic hypertension whose DBPs were lowered to <70 mm Hg. In those patients whose DBPs were reduced to below 55 mm Hg, the relative risk of cardiovascular events nearly doubled. There are some problems with these data because, again, the numbers of patients who achieved DBP <55 mm Hg were small and a careful reading of this study suggests that levels of 45 mm Hg were not deleterious. These phenomena were noted in the treatment arm but not the placebo arm. It is not clear whether the increased event rate associated with low DBP in the treatment arm was a direct result of diastolic hypotension or, rather, the result of some subclinical disease that was unmasked by antihypertensive therapy. Importantly, the event From the Renal-Electrolyte and Hypertension Division, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA Address for correspondence: Raymond R. Townsend, MD, University of Pennsylvania, 210 White Building, 3600 Spruce Street, Philadelphia, PA 19104 C o m m o n Q u e s t i o n s a n d A n s w e r s i n t h e M a n a g e m e n t o f H y p e r t e n s i o n

Automated Blood Pressure Measurement in Public Places

VOL. 7 NO. 10 OCTOBER 2005 620 Within the past few decades, automated blood pressure (BP) devices began appearing in public places, such as pharmacies and supermarkets, with the goal of detecting undiagnosed, untreated, or inadequately treated hypertension (HTN). The widespread use of such devices in public places raises two important questions: 1) how accurate is this technique in diagnosing HTN? and 2) how effective is this public health strategy in accomplishing its objectives? There are two published guidelines for the validation of automated BP measurement devices, one by the British Hypertension Society1 and one by the American Association for the Advancement of Medical Instrumentation, which has been adopted by the FDA.2 Many automated BP measurement devices are commercially available, yet only a fraction of them have been independently validated.3,4 Furthermore, even among those devices that have been validated in controlled settings, few have been formally tested in the environments in which they are now commonly being used. In one study that used two automated devices in pharmacies in Toronto, Canada, investigators measured the BP of volunteers according to a strict protocol (i.e., seated, after resting for 2 minutes and excluding subjects with large arm circumferences) and found that neither device met criteria for precision according to either the British or American standards.5,6 A similar study, performed in grocery stores in Denver, CO, found the device in question to be inconsistent and inaccurate, with a sensitivity of 26% and a negative predictive value of 45% for diagnosing HTN.7 The accuracy of such devices is even more uncertain when utilized in an uncontrolled fashion where there is no standardization for subject position (i.e., sitting vs. standing), arm position (i.e., at the level of the heart), activity level (i.e., at rest), noise level, and arm circumference. Indeed, based on data from the Third National Health and Nutrition Examination Survey (NAHNES III), it is estimated that nearly half of all Americans with HTN have arm circumferences above the limits of one commonly used device.8 Only one study we could find has attempted to measure the efficacy of this public health strategy as a screening tool.9 In this study, automated devices were placed in 13 public places in Exeter, England (including post offices, supermarkets, and homeless shelters) for up to 18 weeks. Of the 769 people who used the devices, 221 recorded elevated BPs (defined as >135/85 mm Hg or systolic BP >160 mm Hg), among whom only 58 were available for follow-up and only 36 subsequently had formal BP measurements by a health care provider. Of this group, 11 subjects (1.4% of all users) were diagnosed with HTN, five of whom started antihypertensive therapy. Another 11 subjects were identified with inadequately treated HTN and five had adjustments made to their antihypertensive regimen, although it is unclear as to whether these From the Department of Medicine, Hypertension Program, University of Pennsylvania School of Medicine, Philadelphia, PA Address for correspondence: Raymond R. Townsend, MD, Department of Medicine, Hypertension Program, University of Pennsylvania School of Medicine, White Building, 3400 Spruce Street, Philadelphia, PA 19104 C o m m o n Q u e s t i o n s a n d A n s w e r s i n t h e M a n a g e m e n t o f H y p e r t e n s i o n

Routine Measurement of Plasma Renin Activity in the Management of Patients With Essential Hypertension: Notes From the 19th Annual ASH Meeting

VOL. VI NO. XII DECEMBER 2004 720 At the 19th annual meeting of the American Society of Hypertension, an afternoon symposium was devoted to the “Laragh method” of hypertension (HTN) management. This method is based on the principle that “HTN is caused by an abnormal relationship between plasma renin and body salt.”1 In other words, HTN is a spectrum with two “polar extremes”: primary hyperaldosteronism, which is a salt-sensitive form of HTN with low plasma renin activity (PRA) (i.e., volume mediated or “V”) and renin-mediated malignant HTN with a high PRA (i.e., “R”). Thus patients with essential HTN fall within this spectrum and can have primarily “V” type HTN, primarily “R” type HTN, or a combination thereof. Likewise, the management scheme proposes that antihypertensive drugs can be divided into two categories: diuretics (i.e., “V” drugs, including thiazide, loop and potassium sparing diuretics, as well as calcium channel blockers and α blockers) and drugs that interrupt the renin-angiotensin-aldosterone axis (i.e., “R” drugs including angiotensin-converting enzyme inhibitors [ACEIs], angiotensin receptor blockers, β blockers, clonidine, reserpine, and α-methyldopa). The simplest way to determine if a given hypertensive patient is a “V” or an “R” patient, requiring a “V” or an “R” drug, respectively, is to measure the PRA. Consequently, this approach mandates the testing of PRA in every hypertensive patient to determine both the initial selection of antihypertensive therapy as well to guide subsequent adjustment of the medication regimen.2,3 Here is a summary of this method: “V” patients will have a PRA <0.65 ng/mL/h and should be started on a “V” drug. If the patient’s blood pressure (BP) is not adequately controlled after several weeks, the PRA should again be checked. If it is still suppressed, a second “V” drug should be added. If, however, it is elevated (>0.65 ng/mL/h), an “R” drug should be added to the regimen. “R” patients, on the other hand, will have an initial PRA >0.65 ng/mL/h and should be started on an “R” drug. If their BP is not adequately controlled after several weeks, then their PRA should be checked again. An ACEI or angiotensin receptor blocker would be expected to induce a nearly 10-fold rise in the PRA. Thus, if the PRA is now >6.5 ng/mL/h, a second “R” drug should be added. If, however, the PRA is <6.5 ng/mL/h, then a “V” drug should be added to the regimen. This method is supposed to predict that the addition of a diuretic (or low-salt diet) to a patient with pure “R” HTN may induce a paradoxical rise in BP! There are several caveats to this method. First, the protocol does not address drug dosage. In other From the Renal-Electrolyte and Hypertension Division, Department of Medicine, Hypertension Program, University of Pennsylvania School of Medicine, Philadelphia, PA Address for correspondence: Raymond R. Townsend, MD, Department of Medicine, Hypertension Program, University of Pennsylvania School of Medicine, 201 White Building, 3400 Spruce Street, Philadelphia, PA 19104 C o m m o n Q u e s t i o n s a n d A n s w e r s i n t h e M a n a g e m e n t o f H y p e r t e n s i o n

What time of day should I take my antihypertensive medications

THE JOURNAL OF CLINICAL HYPERTENSION 593 Physicians have long noted that cardiovascular events more commonly occur in the morning. Indeed, analysis of the Framingham data1 has demonstrated that the incidence of sudden cardiac death is 70% higher between 7 a.m. and 9 a.m. than during the rest of the day. Additionally, a meta-analysis of 30 studies including over 60,000 patients has shown that the incidence of myocardial infarction is 40% greater between the hours of 6 a.m. and 12 p.m. than during the rest of the day.2 Similarly, stroke and ventricular arrhythmias occur with greater frequency in the morning hours. Such cyclic variations in cardiovascular events have been attributed to the circadian nature of our biologic clocks, known as “chronobiology.” Specifically, plasma catecholamines and cortisol, as well as vascular tone and effective circulating volume, are highest in the morning, accounting for the morning blood pressure (BP) increase (approximately 3/2 mm Hg), and with it a higher incidence of cardiac events. One obvious question that arises is: Should we dose antihypertensive agents in such a fashion (i.e., at bedtime for standard daily drugs and nighttime for extended-release preparations) so that their peak activity coincides with, and perhaps blunts the morning increase in BP? Such a treatment strategy is referred to as “chronotherapeutics.” It is important to note that impressive reductions in cardiovascular end points have been demonstrated in numerous clinical trials in which BP lowering agents have not been given at night but have routinely been administered in the morning. Nevertheless, the issue at hand is whether we might further reduce the incidence of these end points by dosing antihypertensive agents at night. Several small studies have looked specifically at BP responses with nocturnal compared with morning dosing of various agents. These studies were previously reviewed in this journal.3 One small study demonstrated better nocturnal BP control with nightly compared with morning dosing of the angiotensin-converting enzyme inhibitor quinapril, though the daytime BPs were similar. Other small studies were unable to show a differential effect in BP of nightly compared with morning dosing of atenolol, nifedipine gastrointestinal therapeutic system, or amlodipine. Notably, none of these small studies looked at long-term cardiovascular end points, such as cardiovascular death, myocardial infarction, or stroke. In the last few years, two large prospective studies were published that assessed cardiovascular end points using nocturnal dosing of antihypertensive agents. The first such study was the Heart Outcomes Prevention Evaluation (HOPE) trial,4 which showed that nightly dosed ramipril (in addition to other medication), compared with a regimen that did not include an angiotensin-converting enzyme inhibitor, significantly decreased all cardiovascular outcomes. One notable observation of the HOPE trial is that only half of the subjects enrolled had hypertension, and only a small part of the benefit was attributed to a reduction in BP. Though some attribute these results to possible cardioprotective properties of angiotensin-converting enzyme inhibitors above and beyond their From the Renal-Electrolyte and Hypertension Division, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA Address for correspondence: Raymond R. Townsend, MD, University of Pennsylvania, 210 White Building, 3600 Spruce Street, Philadelphia, PA 19104 C o m m o n Q u e s t i o n s a n d A n s w e r s i n t h e M a n a g e m e n t o f H y p e r t e n s i o n