Ellen Burgess

High levels of proteinuria predict renal deterioration, suggesting that interventions to reduce proteinuria may postpone the development of severe renal impairment. This multicenter Canadian trial evaluated whether supramaximal dosages of candesartan would reduce proteinuria to a greater extent than the maximum approved antihypertensive dosage. The authors randomly assigned 269 patients who had persistent proteinuria (≥1 g/d) despite 7 wk of treatment with the highest approved dosage of candesartan (16 mg/d) to 16, 64, or 128 mg/d candesartan for 30 wk. The median serum creatinine level was 130.0 μmol/L (1.47 mg/dl), and the median urinary protein excretion was 2.66 g/d; most (53.9%) patients had diabetic nephropathy. The mean difference of the percentage change in proteinuria for patients receiving 128 mg/d candesartan compared with those receiving 16 mg/d candesartan was −33.05% (95% confidence interval −45.70 to −17.44; P < 0.0001). Reductions in BP were not different across the three treatment groups. Elevated serum potassium levels (K⁺ > 5.5 mEq/L) led to the early withdrawal of 11 patients, but there were no dosage-related increases in adverse events. In conclusion, proteinuria that persists despite treatment with the maximum recommended dosage of candesartan can be reduced by increasing the dosage of candesartan further, but serum potassium levels should be monitored during treatment.

Appreciation of the role of aldosterone in cardiovascular and renal disease has increased in the last 50 years. The use of spironolactone was limited by adverse sexual effects, including gynaecomastia. Eplerenone is a newer aldosterone antagonist that is much more selective, with minimal affinity for progesterone and androgenic receptors; therefore, there are very few reports of adverse sexual effects. A review of published trials shows that eplerenone reduces blood pressure (BP) in a dose-dependent manner, from 50 to 200 mg/day, and to a similar degree as enalapril. It has an additive effect when given to patients inadequately controlled on an angiotensin-converting enzyme inhibitor or an angiotensin-receptor blocker. Eplerenone performs better than losartan in African-American patients and lowers BP regardless of initial plasma renin activity. The risk of hyperkalaemia is low, similar to that of enalapril, and < 1% of patients have had to be withdrawn from studies because of elevated serum potassium lev...

Perindopril, an angiotensin-converting enzyme (ACE) inhibitor, is a well-recognized antihypertensive drug. Its ability to protect against cardiovascular events in hypertension has also been demonstrated. It decreases the stiffness of the larger arteries; questions remain as to the mechanisms involved and whether it is blood pressure (BP) control-dependent. To correlate the BP response to ACE inhibition therapy with changes in arterial stiffness as evaluated by pulse wave velocity (PWV), and to correlate these changes in arterial stiffness with alterations in indicators of vascular collagen metabolism serum levels of metalloproteinase (MMP)-1 and tissue inhibitor of MMP-1 (TIMP-1). A total of 162 patients aged 18 to 70 years with stage 1 and 2 essential hypertension (diastolic BP 95 mmHg to 114 mmHg) were enrolled to receive six months (M6) of therapy with the ACE inhibitor, perindopril. Patients were either treatment-naïve or had not received any antihypertensive treatment for at least six months before the study. Mean BP was significantly reduced after two months (M2) of therapy (P=0.00001) and remained stable thereafter. In addition to the significant mean changes in PWV observed at M2 (P=0.00001), further reductions in PWV were noted at M6 (P=0.007). The change in PWV between baseline (M0) and M2 was significantly correlated to all BP parameters at M0 (correlation coefficient at M2 was 0.189 or greater). However, no correlation was seen regarding BP parameters at M2 and further M2 to M6 changes in PWV, suggesting a decrease of arterial stiffness independent of BP reduction. The expression of TIMP-1 and MMP-1 was highly variable and demonstrated no correlation with BP or PWV. Reductions in BP and PWV appear to be correlated during the first two months of perindopril therapy. After six months, PWV continues to decrease independently of any further reduction in BP, suggesting the occurrence of a pressure-independent pharmacological remodelling of the arterial wall. A long-term, double-blind, randomized trial could be required to confirm that the observed increase in vascular distensibility induced by perindopril is related to a mechanism of action other than a reduction in BP.

The Reduction of Endpoints in NIDDM [non-insulin-dependent diabetes mellitus] with the Angiotensin II Antagonist Losartan (RENAAL) study demonstrated the renoprotective effects of losartan in patients with nephropathy from type 2 diabetes. To perform an economic evaluation of the costs associated with end-stage renal disease (ESRD) from a Canadian public health perspective, based on the clinical outcomes reported in the RENAAL study. ESRD-related costs were determined by estimating the mean number of days with ESRD multiplied by the daily cost of ESRD (140 dollars); mean days with ESRD were calculated by subtracting the area under the Kaplan-Meier survival curve for time to the first event of ESRD or all-cause mortality from the area under the curve for all-cause mortality. Daily ESRD cost was determined using Canadian specific data sources. ESRD-related cost savings with losartan were obtained by subtracting the ESRD-related costs of the losartan group from those of the placebo group. Net cost savings were ESRD-related cost savings with losartan minus the drug cost of losartan. Losartan reduced the number of ESRD days by 33.6 per patient over 3.5 years (95% CI 10.9 to 56.3) compared with placebo. Losartan reduced ESRD-related costs by 4,695 dollars per randomized patient over 3.5 years (95% CI 1,523 dollars to 7,868 dollars). After accounting for the drug cost of losartan, net cost savings with losartan were 3,675 dollars per randomized patient over 3.5 years. Losartan therapy for patients with nephropathy from type 2 diabetes reduces the clinical incidence of ESRD and can result in considerable cost savings for the Canadian public health system.

Background: Recruitment into research studies in the neonatal intensive care unit has been problematic. Therefore suggestions have been made to take decision making about enrolment out of the hands of the parents. Objective: To understand parental perceptions of the process of recruitment and enrolment for research in the neonatal intensive care unit. Method: A questionnaire was developed and used in both a retrospective survey and a prospective study of parents whose newborns were enrolled in trials in a neonatal intensive care unit. Closed ended and open ended questions were included, as well as demographic questions. Results: The retrospective survey had a 79% response rate (29 of 38). Overall, 90% of parents felt that they had made informed decisions, and 93% were against the option that a doctor decide if the newborn should be enrolled into a study, rather than the parent. Although some parents (38%) found that recruitment did add “stress to an already stressful situation”, 90% felt that they had made informed decisions and understood the elements of the study. Most parents had been requested to enrol their newborn into more than one trial, and, on average, they thought that they would be comfortable with enrolment into two studies (range 0–6). When asked how the process could be improved, parents suggested that information be made available before delivery. The responses of parents in the prospective study were mostly consistent with those from the retrospective survey. Conclusions: Overall the parents did not support the suggestion that decision making about enrolment be taken away from parents and put into the hands of doctors. The healthcare team should support parents in their role of decision maker, enhance availability of the research staff, and provide more information about the research.

Selective cyclo-oxygenase (COX)-2 inhibitors (coxibs) produce the beneficial effects of nonsteroidal anti-inflammatory drugs (NSAIDs) while sparing the COX-1-mediated adverse effects on platelets and the gastrointestinal system. However, due to the presence of constitutive COX-2 in the human kidney, coxibs have the same potential for adverse renal effects as traditional NSAIDs. To provide evidence-based guidelines for the use of traditional NSAIDs and coxibs in patients potentially at risk for renal and associated hemodynamic blood pressure effects. All pertinent peer-reviewed papers were retrieved with the usual electronic search tools. Both traditional NSAIDs and coxibs compromise the glomerular filtration rate in patients at increased risk. If there are differences in the blood pressure-raising potential of these drugs, these differences do not appear to be clinically significant. The blood pressure should be monitored for all patients taking chronic NSAID or coxib therapy. If a clinically significant (4 to 5 mmHg or more) increase in blood pressure is detected, the NSAID or the coxib should be discontinued and replaced with acetaminophen, to which codeine might be added. If the NSAID or the coxib is considered necessary, the increase in blood pressure should be treated. In addition, if the glomerular filtration rate reserve is compromised, all patients (including those taking short term therapy) should be closely monitored for the early detection of signs and symptoms of renal failure.

To provide updated, evidence-based recommendations for the assessment of the diagnosis, cardiovascular risk, identifiable causes and lifestyle modifications for adults with high blood pressure. For persons in whom a high blood pressure value is recorded, hypertension is diagnosed based on the appropriate measurement of blood pressure, the level of the blood pressure elevation and the duration of follow-up. In addition, the presence of concomitant vascular risk factors, target organ damage and established atherosclerotic diseases must be assessed to determine the urgency, intensity and type of treatment. For persons receiving a diagnosis of hypertension, defining the overall risk of adverse cardiovascular outcomes requires an assessment of concomitant vascular risk factors, including laboratory testing, a search for target organ damage and an assessment for modifiable causes of hypertension. Home and ambulatory blood pressure assessment and echocardiography are options for selected patients. The outcomes were: the identification of persons at increased risk of adverse cardiovascular outcomes; the quantification of overall cardiovascular risk; and the identification of persons with potentially modifiable causes of hypertension. Medline searches were conducted from one year before the period of the last revision of the Canadian recommendations for the management of hypertension (May 1999 to May 2001). Reference lists were scanned, experts were polled, and the personal files of the subgroup members and authors were used to identify other studies. Identified articles were reviewed and appraised, using prespecified levels of evidence, by content experts and methodological experts. In addition to an update of the previous year's review, new sections on assessing overall cardiovascular risk and endocrine causes are provided. A high value was placed on the identification of persons at increased risk of cardiovascular morbidity and mortality, and of persons with identifiable causes of hypertension. The identification of persons at higher risk of cardiovascular disease will permit counseling for lifestyle manoeuvres and introduction of antihypertensive drugs to reduce blood pressure for patients with sustained hypertension. The identification of specific causes of hypertension may permit the use of cause-specific interventions. In certain subgroups of patients, and for specific classes of drugs, blood pressure lowering has been associated with reduced cardiovascular morbidity or mortality. The present document contains recommendations for the assessment of the diagnosis, cardiovascular risk, identifiable causes and lifestyle modifications for adults with high blood pressure. These include the accurate measurement of blood pressure, criteria for the diagnosis of hypertension and recommendations for follow-up, assessment of overall cardiovascular risk, routine and optional laboratory testing, assessment for renovascular and endocrine causes, home and ambulatory blood pressure monitoring, the role of echocardiography and lifestyle modifications. All recommendations were graded according to the strength of the evidence and voted on by the Canadian Hypertension Recommendations Working Group. Only those recommendations achieving high levels of consensus are reported. These guidelines will be updated annually. These guidelines are endorsed by the Canadian Hypertension Society, The Canadian Coalition for High Blood Pressure Prevention and Control, The College of Family Physicians of Canada, The Heart and Stroke Foundation of Canada, The Adult Disease Division and Bureau of Cardio-Respiratory Diseases and Diabetes at the Centre for Chronic Disease Prevention and Control, Health Canada.

To provide updated, evidence-based recommendations for the therapy of hypertension in adults. For patients with hypertension, a number of antihypertensive agents may control blood pressure. Randomized trials evaluating first-line therapy with thiazides, beta-adrenergic antagonists, angiotensin-converting enzyme inhibitors, calcium channel blockers, alpha-blockers, centrally acting agents or angiotensin II receptor antagonists were reviewed. The health outcomes that were considered were changes in blood pressure, cardiovascular morbidity, and cardiovascular and/or all-cause mortality rates. Economic outcomes were not considered due to insufficient evidence. MEDLINE was searched for the period March 1999 to October 2001 to identify studies not included in the 2000 revision of the Canadian Recommendations for the Management of Hypertension. Reference lists were scanned, experts were polled, and the personal files of the subgroup members and authors were used to identify other published studies. All relevant articles were reviewed and appraised, using prespecified levels of evidence, by content experts and methodological experts. A high value was placed on the avoidance of cardiovascular morbidity and mortality. Various antihypertensive agents reduce the blood pressure of patients with sustained hypertension. In certain settings, and for specific classes of drugs, blood-pressure lowering has been associated with reduced cardiovascular morbidity and/or mortality. The present document contains detailed recommendations pertaining to treatment thresholds, target blood pressures, and choice of agents in various settings in patients with hypertension. The main changes from the 2000 Recommendations are the addition of a section on the treatment of hypertension in patients with diabetes mellitus, the amalgamation of the previous sections on treatment of hypertension in the young and old into one section, increased emphasis on the role of combination therapies over repeated trials of single agents and expansion of the section on the treatment of hypertension after stroke. Implicit in the recommendations for therapy is the principle that treatment for an individual patient should take into consideration global cardiovascular risk, the presence and/or absence of target organ damage, and comorbidities. All recommendations were graded according to strength of the evidence and voted on by the Canadian Hypertension Recommendations Working Group. Individuals with potential conflicts of interest relative to any specific recommendation were excluded from voting on that recommendation. Only those recommendations achieving high levels of consensus are reported here. These guidelines will continue to be updated annually.