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Henry Krum

Publications and source records attributed to Henry Krum.

At least 19 recordsLinked to original sources
PubMed2007

Novel therapies blocking the renin-angiotensin-aldosterone system in the management of hypertension and related disorders.

Although significant advances have been made in the therapeutic blockade of the renin-angiotensin-aldosterone system (RAAS) using angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers and non-selective aldosterone receptor antagonists, there is a clear need for both additional blocking strategies and enhancements of current therapeutic approaches. Vasopeptidase inhibition may still find a role despite the small incremental value of this approach and the obvious issue of kinin-mediated adverse effects still to be fully addressed. Blockade of the RAAS upstream using renin inhibitors as well as the greater selectivity of aldosterone blockade using selective aldosterone blockers such as eplerenone are also novel approaches. Not yet in clinical use but certainly an attractive therapeutic target is angiotensin II growth factor receptor transactivation, with selective inhibitors having been developed for various specific kinase pathways. Finally, ACE2 augmentation, antisense gene strategies, and vaccination against the renin-angiotensin system should still be considered experimental, but have significant appeal as additional approaches to the blockade of this system.

Angiotensin II↗
PubMed2007

Clozapine-associated myocarditis: a review of 116 cases of suspected myocarditis associated with the use of clozapine in Australia during 1993-2003.

BACKGROUND: Clozapine is an antipsychotic medication associated with a lower suicide rate compared with other antipsychotic agents. Clozapine is used specifically in patients for whom previous therapy was inadequate or not tolerated, and is the only antipsychotic agent associated with the development of myocarditis. OBJECTIVE: To retrospectively review all adverse drug reaction reports voluntarily submitted to the Australian Adverse Drug Reactions Unit mentioning suspected myocarditis in clozapine-treated patients. PATIENTS AND METHODS: We accessed all electronic database entries and case reports citing suspected myocarditis associated with clozapine therapy from January 1993 through to December 2003, inclusive. RESULTS: 116 case reports of suspected myocarditis amongst clozapine-treated patients were identified during the specified time frame (incidence between 0.7% and 1.2% of treated patients). Median patient age for these cases was 30 years (SD 11.1 years) compared with 37 years from the Clopine registry. The condition developed within a median 16 days (mean 19.8 days; SD 17.3 days) of commencing clozapine for the bulk of patients developing myocarditis within 6 months (n=93, 80.2%). For all cases with known treatment commencement and cessation dates (n=106), the condition developed within a median 17 days (mean 171.7 days, SD 530.9 days). Over nine-tenths of cases were prescribed clozapine within the dose range of 100 mg/day to 450 mg/day. Sixty patients (51.8%) recovered from their episode when reported or during follow-up reports, whereas 17 patients (14.7%) had not yet recovered: 27 patients (23.3%) had unknown outcome when reported and the remaining 12 patients (10.3%) died. CONCLUSION: Clozapine is uncommonly but importantly related to myocarditis, often fatal or near fatal and sometimes in relatively young patients with early onset after treatment initiation. The most striking feature about this condition is the wide diversity of nonspecific symptoms that occur in afflicted patients. Additional pharmacovigilance, improved reporting systems and further investigation of mechanisms of drug-induced myocarditis and related cardiovascular conditions (such as heart failure) are clearly warranted. A case-control study would be suitable for investigation of baseline predictors.

Adult↗
PubMed2006

Guidelines for the prevention, detection and management of people with chronic heart failure in Australia 2006.

Chronic heart failure (CHF) is found in 1.5%-2.0% of Australians. Considered rare in people aged less than 45 years, its prevalence increases to over 10% in people aged >/= 65 years. CHF is one of the most common reasons for hospital admission and general practitioner consultation in the elderly (>/= 70 years). Common causes of CHF are ischaemic heart disease (present in > 50% of new cases), hypertension (about two-thirds of cases) and idiopathic dilated cardiomyopathy (around 5%-10% of cases). Diagnosis is based on clinical features, chest x-ray and objective measurement of ventricular function (eg, echocardiography). Plasma levels of B-type natriuretic peptide (BNP) may have a role in diagnosis, primarily as a test for exclusion. Diagnosis may be strengthened by a beneficial clinical response to treatment(s) directed towards amelioration of symptoms. Management involves prevention, early detection, amelioration of disease progression, relief of symptoms, minimisation of exacerbations, and prolongation of survival.

Aftercare↗
PubMed2006

Cardiovascular outcomes with etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme: a randomised comparison.

BACKGROUND: Cyclo-oxygenase-2 (COX-2) selective inhibitors have been associated with an increased risk of thrombotic cardiovascular events in placebo-controlled trials, but no clinical trial has been reported with the primary aim of assessing relative cardiovascular risk of these drugs compared with traditional non-steroidal anti-inflammatory drugs (NSAIDs). The MEDAL programme was designed to provide a precise estimate of thrombotic cardiovascular events with the COX-2 selective inhibitor etoricoxib versus the traditional NSAID diclofenac. METHODS: We designed a prespecified pooled analysis of data from three trials in which patients with osteoarthritis or rheumatoid arthritis were randomly assigned to etoricoxib (60 mg or 90 mg daily) or diclofenac (150 mg daily). The primary hypothesis stated that etoricoxib is not inferior to diclofenac, defined as an upper boundary of less than 1.30 for the 95% CI of the hazard ratio for thrombotic cardiovascular events in the per-protocol analysis. Intention-to-treat analyses were also done to assess consistency of results. These trials are registered at http://www.clinicaltrials.gov with the numbers NCT00092703, NCT00092742, and NCT00250445. FINDINGS: 34 701 patients (24 913 with osteoarthritis and 9 787 with rheumatoid arthritis) were enrolled. Average treatment duration was 18 months (SD 11.8). 320 patients in the etoricoxib group and 323 in the diclofenac group had thrombotic cardiovascular events, yielding event rates of 1.24 and 1.30 per 100 patient-years and a hazard ratio of 0.95 (95% CI 0.81-1.11) for etoricoxib compared with diclofenac. Rates of upper gastrointestinal clinical events (perforation, bleeding, obstruction, ulcer) were lower with etoricoxib than with diclofenac (0.67 vs 0.97 per 100 patient-years; hazard ratio 0.69 [0.57-0.83]), but the rates of complicated upper gastrointestinal events were similar for etoricoxib (0.30) and diclofenac (0.32). INTERPRETATION: Rates of thrombotic cardiovascular events in patients with arthritis on etoricoxib are similar to those in patients on diclofenac with long-term use of these drugs.

Aged↗
PubMed2006

Statins and symptomatic chronic systolic heart failure: a post-hoc analysis of 5010 patients enrolled in Val-HeFT.

BACKGROUND: Statins prolong survival in patients at high risk for cardiovascular events, however little is known regarding their efficacy and safety in patients with established chronic heart failure (CHF). To address this, we retrospectively analyzed the Valsartan Heart Failure Trial (Val-HeFT) database to determine outcomes in CHF patients according to statin use at baseline. METHODS: Demographic characteristics of patients receiving statins at baseline (n=1602) were compared with those who were not (n=3048). A multivariate Cox proportional hazards model, with death as outcome, was used to assess the impact of statin therapy, with adjustment made for baseline differences in relevant parameters. RESULTS: Patients receiving statins at baseline were younger with fewer females, fewer in NYHA III-IV, more with an ischemic etiology, more diabetics, higher BMI, lower SBP, more on beta-blockers, but no difference in LVEF or ACEi use. Mortality over a mean 2-year follow-up was 17.9% on statins versus 20.3% without statins (p=0.029). Cox-adjusted hazard ratio for statins was 0.81 [95% CI 0.70-0.94]. No statistically significant interaction was found between statins and valsartan for mortality. After 4 months, the only laboratory changes were a reduction in CRP and an attenuation of the rise in norepinephrine in the statin group. CONCLUSIONS: In a large, contemporary sample of patients with CHF, statin use appeared to be associated with a lower 2-year mortality. These findings suggest a prognostic benefit for statins in established CHF, however prospective data are required to definitively address this issue. CONDENSED ABSTRACT: We examined major cardiovascular outcomes in patients who were (n=1602) and were not (n=3048) receiving statins at baseline in the Val-HeFT cohort of patients with mild to moderate systolic chronic heart failure. Mortality was reduced in patients receiving statins compared to those who were not, without any significant interaction effect between statin treatment and valsartan. These findings suggest a prognostic benefit for statins in established heart failure, however prospective data are required to definitively address this issue.

Aged↗
PubMed2006

Impact of statin therapy on clinical outcomes in chronic heart failure patients according to beta-blocker use: results of CIBIS II.

BACKGROUND: HMG-CoA reductase inhibitors (statins) are widely prescribed in patients with established systolic chronic heart failure (CHF). However, there is considerable controversy regarding their benefit in this setting. We therefore conducted a post-hoc analysis of outcomes according to statin use within the Second Cardiac Insufficiency Bisoprolol Study of the beta-blocker, bisoprolol, in NYHA classes III-IV systolic CHF patients (left ventricular ejection fraction <35%), receiving background ACE inhibitor and diuretics. METHODS: Analysis of clinical outcomes was performed according to baseline use of statins and subsequent randomisation to placebo or bisoprolol. Cumulative incidence curves for clinical events were constructed using the Kaplan-Meier method and tested for significance by log-rank statistic. Multivariate analysis was performed using the Cox proportional hazards regression model. RESULTS: Two hundred and twenty-six of 2,647 patients were receiving statins at baseline (8.5%). Patients were well-matched in the 4 study groups at baseline for gender, weight, NYHA class and LVEF, however statin/bisoprolol patients were significantly younger (p < 0.05). Statin use at baseline was associated with a significant survival benefit compared with no statin use (p < 0.005, hazard ratio [HR] = 0.60, 95% confidence interval [CI] = 0.39-0.94). This benefit remained after adjusting for other significant predictors of survival (p < 0.05, HR = 0.60, 95%CI = 0.39-0.94). A significant interaction effect was noted with bisoprolol, survival being greatest in the statin/bisoprolol group (p < 0.001, HR = 0.14, 95% CI = 0.03-0.60). Survival was 98.3% in the statin/bisoprolol group, 82.1% in the statin/placebo group, 87.2% in the no statin/bisoprolol group and 82.8% in the no statin/placebo group. The statin/bisoprolol group was also associated with fewer cardiovascular (p < 0.005) and sudden deaths (p < 0.0005) compared with other groups. CONCLUSIONS: Despite the post-hoc, non-randomised nature of this analysis, these observations suggest that statin use appears to be beneficial in CHF. Furthermore, there appears to be a favourable interaction between statins and beta-blockade within the Second Cardiac Insufficiency Bisoprolol Study cohort. Prospective studies of statins are required to definitively address the role of these agents in established CHF.

Adrenergic beta-Antagonists↗
PubMed2006

Does the presence of heart failure alter prescribing of drug therapy after myocardial infarction? A multicentre study.

OBJECTIVE: To evaluate the use of cardiovascular medications in patients with and without heart failure after myocardial infarction (MI). DESIGN AND SETTING: Multicentre study of drug therapy for patients with MI in 16 major metropolitan teaching hospitals in Australia over a 1-month period at each hospital in the period November 2004 - March 2005. PARTICIPANTS: 479 patients admitted consecutively to the individual hospitals. MAIN OUTCOME MEASURES: Proportion of patients with and without heart failure who were prescribed key cardiovascular medications after MI. RESULTS: 116 of the 479 patients admitted for MI (24.2%) had heart failure at some point during their hospitalisation. Patients with heart failure were older (68 v 63 years; P < 0.05), more likely to be women (34% v 24%; P < 0.05) and a higher proportion had diabetes (26% v 21%). There was significantly reduced prescribing of beta-blockers, clopidogrel and statins for patients with heart failure compared with those without heart failure. Mineralocorticoid receptor antagonist use was low (< 10%) in the former group. CONCLUSIONS: We found reduced prescribing of some prognostically relevant medications for patients with heart failure. For beta-blockers, this may be explained by the greater clinical instability in patients with heart failure. Given the absolute benefit of drug therapy in patients with heart failure after MI, our findings suggest suboptimal prescribing in Australian teaching hospital practice.

Aged↗
PubMed2006

Aldosterone blockade in post-acute myocardial infarction heart failure.

Development of heart failure (HF) or left ventricular systolic dysfunction (LVSD) significantly increases mortality post acute myocardial infarction (AMI). Aldosterone contributes to the development and progression of HF post AMI, and major guidelines now recommend aldosterone blockade in this setting. However, lack of practical experience with aldosterone blockade may make clinicians hesitant to use these therapies. This review is based on a consensus cardiology conference that occurred in May 2005 (New York City) concerning these topics. Potential barriers to the use of aldosterone blockade are discussed and an algorithm for appropriate in-hospital pharmacologic management of AMI with LVSD and/or HF is presented.

Algorithms↗
PubMed2006

Are beta-blockers needed in patients receiving spironolactone for severe chronic heart failure? An analysis of the COPERNICUS study.

BACKGROUND: The beneficial effects of beta-blockers and aldosterone receptor antagonists are now well established in patients with severe systolic chronic heart failure (CHF). However, it is unclear whether beta-blockers are able to provide additional benefit in patients already receiving aldosterone antagonists. We therefore examined this question in the COPERNICUS study of 2289 patients with severe CHF receiving the beta1-beta2/alpha1 blocker carvedilol compared with placebo. METHODS: Patients were divided post hoc into subgroups according to whether they were receiving spironolactone (n = 445) or not (n = 1844) at baseline. Consistency of the effect of carvedilol versus placebo was examined for these subgroups with respect to the predefined end points of all-cause mortality, death or CHF-related hospitalizations, death or cardiovascular hospitalizations, and death or all-cause hospitalizations. RESULTS: The beneficial effect of carvedilol was similar among patients who were or were not receiving spironolactone for each of the 4 efficacy measures. For all-cause mortality, the Cox model hazard ratio for carvedilol compared with placebo was 0.65 (95% CI 0.36-1.15) in patients receiving spironolactone and 0.65 (0.51-0.83) in patients not receiving spironolactone. Hazard ratios for death or all-cause hospitalization were 0.76 (0.55-1.05) versus 0.76 (0.66-0.88); for death or cardiovascular hospitalization, 0.61 (0.42-0.89) versus 0.75 (0.64-0.88); and for death or CHF hospitalization, 0.63 (0.43-0.94) versus 0.70 (0.59-0.84), in patients receiving and not receiving spironolactone, respectively. The safety and tolerability of treatment with carvedilol were also similar, regardless of background spironolactone. CONCLUSION: Carvedilol remained clinically efficacious in the COPERNICUS study of patients with severe CHF when added to background spironolactone in patients who were practically all receiving angiotensin-converting enzyme inhibitor (or angiotensin II antagonist) therapy. Therefore, the use of spironolactone in patients with severe CHF does not obviate the necessity of additional treatment that interferes with the adverse effects of sympathetic activation, specifically beta-blockade.

Adrenergic beta-Antagonists↗
PubMed2006

Noninvasive calibration of cardiac pressure transducers in patients with heart failure: an aid to implantable hemodynamic monitoring and therapeutic guidance.

BACKGROUND: Implantable cardiac pressure monitors require assurance of calibration. This study evaluated if airway pressure responses during Valsalva maneuver (VM) can be used for calibrating intracardiac pressure transducers. METHODS AND RESULTS: Thirty-eight heart failure patients performed VMs while cardiac and airway pressures were recorded. Patients were designated as Lower (L) if baseline PCW was <20 mm Hg (n = 17); otherwise, they were categorized as Higher (H) (n = 21). VMs were repeated in 9 H patients after nitroglycerin. Procedural success was 92% and there were no complications. Differences between filling pressure and airway pressure (effective pressure) were eliminated during VM (RA(eff) = -0.9 +/- 1.3, RVED(eff) = 1.2 +/- 1.1, PCW(eff) = 2.1 +/- 2.8, and LVED(eff) = 0.9 +/- 1.6 mm Hg), and filling pressures were highly correlated with airway pressure r = 0.94. On average, group H had higher PCW(eff) and LVED(eff) than L patients by 1.8 and 2.5 mm Hg (P < or = .002), respectively, but after nitrates their responses were identical. CONCLUSION: The relationships between cardiac filling pressure and airway pressure during the Valsalva maneuver are sufficiently reliable to be considered as a new, noninvasive method for establishing the calibration of cardiac pressure sensors in patients with heart failure.

Aged↗
PubMed2006

Blood pressure effects of COX-2 inhibitors.

There has been significant recent interest in the cardiovascular effects of cyclooxygenase 2 (COX-2) selective inhibitors. Whereas much attention has been focused on the putative prothrombotic effect of these agents, their cardiorenal and blood pressure elevating actions may be of equal if not greater importance to cardiovascular risk. COX-2 is widely expressed throughout the kidney, and inhibition of this enzyme is contributory to reduced glomerular filtration, salt and water retention, and blood pressure elevation. The key issues in relation to COX-2 inhibitors and blood pressure are whether these blood pressure-elevating effects are similar to or differ from nonselective nonsteroid anti-inflammatory drugs, whether differences exist among COX-2 inhibitors in regard to blood pressure regulation, and if so, possible mechanisms underlying blood pressure differences between COX-2 inhibitors. With regard to the last issue, possible mechanisms include greater COX-2 selectivity of certain agents such as rofecoxib, the differing half-life of these agents, the carbonic anhydrase activity of celecoxib (which may offset renal-induced salt and water retention), and possible aldosterone modulation by rofecoxib. Finally, and perhaps most important, the issue arises as to whether blood pressure elevation may contribute in whole or in part to the increase in cardiovascular events observed with these agents in some but not all studies. Ultimately, adequately powered, prospective randomized clinical trials assessing relevant cardiovascular endpoints are required to address many of these outstanding questions. Such studies have recently been announced and will commence soon.

Animals↗
PubMed2006

Drug therapy of chronic heart failure in the elderly: the current state of clinical-trial evidence.

PURPOSE OF REVIEW: beta-Blockers, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, aldosterone receptor antagonists, and digoxin are the most common drug classes used to treat chronic heart failure. We examine current clinical trial evidence concerning heart-failure management in the elderly. RECENT FINDINGS: beta-Blockers provide significant mortality benefit to elderly heart-failure patients and are remarkably well tolerated. Angiotensin-converting-enzyme inhibitors improve mortality and morbidity in systolic heart failure. However, the risk/benefit relationship of angiotensin-converting-enzyme therapy in the elderly has not been adequately determined. Angiotensin II receptor blockers improve morbidity in elderly and non-elderly chronic heart-failure patients; however, data are limited regarding mortality in these patients. Aldosterone receptor antagonists provide significant mortality benefit to elderly chronic heart-failure patients. Digoxin is beneficial as an additive therapy in the treatment of systolic heart failure regardless of advanced age. SUMMARY: Agents that provide substantive clinical benefit overall also appear to do so in the elderly, based on subgroup analysis of major trials. There have been very few prospective, placebo-controlled trials specifically in elderly heart-failure patients. Elderly heart-failure patients generally tolerate standard chronic heart-failure therapies well. Standard chronic heart-failure therapies should not be withheld from elderly patients based on concerns regarding efficacy or fear of medication intolerance.

Adrenergic beta-Antagonists↗
PubMed2006

Can the blood pressure effects of COX-2 selective inhibitors be explained by changes in plasma aldosterone levels?

OBJECTIVE: The increased cardiovascular risk associated with rofecoxib may relate to differential effects on blood pressure (BP) in comparison with other cyclooxygenase-2 (COX-2) selective inhibitors. Rofecoxib is uniquely metabolized by cytosol reductase and may compete with aldosterone for metabolism. We hypothesized that the effect of rofecoxib on BP may be due to an increase in aldosterone levels. DESIGN: Prospective, randomized, cross-over study. SETTING: Tertiary institution. PATIENTS: Eleven patients (all female, age 65 +/- 11 years) with osteoarthritis and hypertension. INTERVENTIONS: Patients received rofecoxib 50 mg once/day or celecoxib 400 mg once/day for 8 weeks, followed by cross-over after a 2-week wash-out period. OUTCOME MEASURES: Office BP, heart rate (HR), plasma aldosterone and aldosterone related-markers, markers of sympathetic and parasympathetic activity, catecholamines and heart rate variability (HRV) were measured. RESULTS: Rofecoxib caused an increase in BP compared to celecoxib; a change in recumbent systolic BP +/- SD (6.1 +/- 11.0 versus -7.0 +/- 12.5 mmHg, P < 0.05) and recumbent diastolic BP +/- SD (3.6 +/- 7.6 versus -1.7 +/- 5.7 mmHg). There was no difference in median change in plasma aldosterone levels between rofecoxib and celecoxib (-31 +/- 171.5 versus 43 +/- 147 pg/ml, P = 0.173). The other parameters measured were not different between the two agents. CONCLUSIONS: Rofecoxib therapy results in a significant increase in systolic BP compared to celecoxib. As plasma aldosterone levels were not different between the two drugs, the differential effect of rofecoxib on BP compared to celecoxib appears to be unlikely due to competition by rofecoxib for aldosterone metabolism.

Aged↗