IV Sotalol - Registry study in children

 85 patients

Age range 1 day - 36 yrs)

Treated with IV Sotalol (Average dose 1 mg/kg/dose; Range = 0.5 - 1.8 mg/kg/dose).

Infused 

over a median period of 60 min (Range 30 min - 5 hours).

Successful in 49%, Improved in 30% (Improved = HR decreased to the extent of allowing overdrive atrial pacing).

QTc prolonged >465 ms in 16% (Prolonged >500 ms in 4%).

Conlcusion: Safe as effective.

Successful or Improved in 79%.

Most common dose is 1 mg/kg/dose, infused over 60 min.

Link to reference: Mollory-walton LE at al. JAHA 2022. 

Mavacamten for HOCM

 FDA approved Mavacamten (Camzyos from Bristol-Myers Squibb) for HOCM for children (May 2022).

Mavacamten is allosteric inhibitor of Myosin

Explorer-HCM trial data showed 

    (i) improved in peak VO2 and 

    (ii) stabilization or improvement in NYHA function class

compared to placebo.

Long-term extension study showed that benefits lasted at 1-year follow up. There was improvement in QoL reported by patients.

Valor-HCM - addition of Mavacamten to maximally-tolerated medical management, reduced the need for surgical or cath intervention for septal reduction.

News from TCTMD dt. 4/29/22

Sildenafil - liquid preparation

Click on the image to enlarge

(10 mg/ml)

New Heart Failure Medication - Sacubitril (Neprilysin inhibitor)

From Cardiology News Aug 2015:

RE: FDA approval for a combination medication (Sacubitril + Valsartan)

Sacubitril - a neprilysin inhibitor

Valsartaion - an angiotensin receptor blocker

Droxidopa (Northera) approved (Feb 2014)

For orthostatic hypotension.
Similar warnings like Midodrine.
Link to this news

Angiotensin Receptor Blocker for Marfan Syndrome

NEJM 2008;358:2787-95

(Click on image to enlarge)

18 pediatric patients were treated (17 received Lorsartan, 1 received Ibesartan).

Age range:1 -16 yrs (median age 6.5 yrs)

Duration of study: Median 6 yrs (~4 yrs before starting ARB & ~ 2 yrs after starting ARB)

Dose:

Losartan - started at 0.6 mg/kg/day x 3 wks. Then, gradually increased to 1.4 mg/kg/day.

Ibesartan - started at 1.4 mg/kg/day. Then, gradually increased to 2.0 mg/kg/day.

Check BUN, Creatinine, Electrolytes after 3 months.

Fenaldopam

Journal List > BMC Anesthesiol > v.8; 2008		Formats: Abstract  |  Full Text  |  PDF (230K)
	BMC Anesthesiol. 2008; 8: 6. Published online 2008 October 6. doi:  10.1186/1471-2253-8-6 PMCID: PMC2576052 Copyright © 2008 Hammer et al; licensee BioMed Central Ltd. Pharmacokinetics and pharmacodynamics of fenoldopam mesylate for blood pressure control in pediatric patients Gregory B Hammer,1 Susan T Verghese,2 David R Drover,3 Myron Yaster,4 and Joseph R Tobin5 1Departments of Anesthesia and Pediatrics, Stanford University School of Medicine, Stanford, USA 2Departments of Anesthesia and Pediatrics, Children's National Medical Center, George Washington University School of Medicine, Washington, USA 3Department of Anesthesia, Stanford University School of Medicine, Stanford, USA 4Departments of Anesthesiology, Critical Care Medicine, and Pediatrics, Johns Hopkins University, Baltimore, USA 5Departments of Anesthesiology and Pediatrics, Wake Forest University School of Medicine, Winston-Salem, USA Corresponding author. Gregory B Hammer: ham@stanford.edu; Susan T Verghese: sverghes@cnmc.org; David R Drover:ddrover@stanford.edu; Myron Yaster: myaster@jhmi.edu; Joseph R Tobin: jtobin@wfubmc.edu Received April 7, 2008; Accepted October 6, 2008. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.  Other Sections▼ Abstract Background Fenoldopam mesylate, a selective dopamine1-receptor agonist, is used by intravenous infusion to treat hypertension in adults. Fenoldopam is not approved by the FDA for use in children; reports describing its use in pediatrics are limited. In a multi-institutional, placebo controlled, double-blind, multi-dose trial we determined the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics and side-effect profile of fenoldopam in children. Methods Seventy seven (77) children from 3 weeks to 12 years of age scheduled for surgery in which deliberate hypotension would be induced were enrolled. Patients were randomly assigned to one of five, blinded treatment groups (placebo or fenoldopam 0.05, 0.2, 0.8, or 3.2 mcg/kg/min iv) for a 30-minute interval after stabilization of anesthesia and placement of vascular catheters. Following the 30-minute blinded interval, investigators adjusted the fenoldopam dose to achieve a target mean arterial pressure in the open-label period until deliberate hypotension was no longer indicated (e.g., muscle-layer closure). Mean arterial pressure and heart rate were continuously monitored and were the primary endpoints. Results Seventy-six children completed the trial. Fenoldopam at doses of 0.8 and 3.2 mcg/kg/min significantly reduced blood pressure (p < 0.05) during the blinded interval, and doses of 1.0–1.2 mcg/kg/min resulted in continued control of blood pressure during the open-label interval. Doses greater than 1.2 mcg/kg/min during the open-label period resulted in increasing heart rate without additional reduction in blood pressure. Fenoldopam was well-tolerated; side effects occurred in a minority of patients. The PK/PD relationship of fenoldopam in children was determined. Conclusion Fenoldopam is a rapid-acting, effective agent for intravenous control of blood pressure in children. The effective dose range is significantly higher in children undergoing anesthesia and surgery (0.8–1.2 mcg/kg/min) than as labeled for adults (0.05–0.3 mcg/kg/min). The PK and side-effect profiles for children and adults are similar

PDE-5 inhibitors - Cardiac Uses

State-of-the-art Review: JACC 2012;59(1):9-15.

Bryan Schwartz et al.

Phosphodiesterase-5 inhibitors (PDE5Is) improve erectile function by enhancing nitric oxide availability in the penis and its supplying vasculature, resulting in vasodilation and increased blood flow. PDE5Is might benefit cardiovascular diseases because phosphodiesterase-5 is also located elsewhere in the body, including the pulmonary and systemic vasculature and in hypertrophied myocardium. PDE5Is are approved for pulmonary arterial hypertension, given that they improved several hemodynamic and clinical parameters in large randomized trials. Initial evidence suggests that PDE5Is benefit patients with congestive heart failure and secondary pulmonary hypertension. PDE5Is seem to improve hemodynamic and clinical parameters in patients with high-altitude pulmonary edema (HAPE) and high-altitude pulmonary hypertension. In climbers with prior episodes of HAPE, PDE5Is prevented HAPE in 2 small randomized trials. In small randomized trials of PDE5Is, patients with Raynaud's phenomenon demonstrated improved blood flow, fewer symptoms and frequency of attacks, and resolution of digital ulcers. In addition to enhancing vasodilation, PDE5Is seem to protect the myocardium through complex pathways that involve nitric oxide, cyclic guanosine monophosphate, protein kinase G, extracellular-signal-regulated kinase, B-cell lymphoma protein-2, and Rho kinase inhibition. In animal models of acute myocardial infarction, PDE5Is consistently reduced infarct size indicating cardioprotection and PDE5Is also promote reverse remodeling and reduce myocardial apoptosis, fibrosis, and hypertrophy. PDE5Is might also benefit patients with treatment-resistant hypertension, preeclampsia, or peripheral arterial disease. This review presents the pathophysiology and trial data with regard to the use of PDE5Is for cardiac diseases.

CLARINET trial

Wessel, D. et al.
(Presented at AHA 2010)

Background: Infants with cyanotic congenital heart disease (CCHD) palliated with a systemic-to-pulmonary artery (PA) shunt are at increased risk for shunt thrombosis and mortality.

Methods: We conducted a multi-center, randomized, double-blind, placebo-controlled trial to determine whether the addition of clopidogrel, 0.2mg/kg/day, to conventional therapy reduces all-cause mortality and shunt-related morbidity in infants with CCHD palliated with a PA shunt. The clopidogrel dose was selected to inhibit ADP-induced platelet aggregation by 30-50%, similar to the 75 mg adult dose. The primary efficacy outcome event was the first occurrence of any component of the composite endpoint of death, shunt thrombosis or a cardiac procedure before 120 days of age following an event considered of thrombotic nature. This event-driven trial conducted in 32 countries had 80% power to detect a 30% relative reduction in the primary event rate with 172 events and .05 overall type I error rate.

Results: 906 infants <3 months of age who had undergone a PA shunt were randomly assigned to receive clopidogrel (467, 51.5%) or placebo (439, 48.5%) in addition to conventional therapy. Median duration of treatment was 162 days. Concomitant aspirin was administered in 88% of subjects.

The primary composite outcome rate did not differ significantly between the clopidogrel vs. placebo groups: 19.1% vs. 20.5%, respectively, with relative risk reduction = 11.1% (95%CI: –19.2, 33.6; p=.43).

Components of the composite primary outcome, analyzed separately, also did not differ significantly between clopidogrel and placebo groups: mortality rate was 11.8% vs 13.9%; shunt thrombosis was 5.8% vs. 4.8%, and cardiac-related interventions occurred in 4.5% vs. 3.2%, respectively.
Clopidogrel treatment was not significantly beneficial within any subgroups, specific cardiac defect groups or shunt types. The percentage of subjects in the clopidogrel vs. placebo groups with any bleeding event (18.8% vs. 20.2%) and with severe bleeding events (4.1% vs. 3.4%) was similar.

Conclusion: Clopidogrel treatment of infants < 3 months of age with CCHD palliated with a PA shunt and predominantly receiving concomitant aspirin therapy does not reduce all-cause mortality or shunt-related morbidity.

PICOLO trial results

Dosing of Clopidogrel for Platelet Inhibition in Infants and Young Children
Primary Results of the Platelet Inhibition in Children On cLOpidogrel (PICOLO) Trial
Jennifer S, Li et al. for the PICOLO Investigators

Circulation 2008;117:553-9

Background— Infants and young children with certain types of heart disease are at increased risk for thromboses. Clopidogrel 75 mg/d is used in adults to prevent thrombotic events. The dose to achieve similar platelet inhibition in children is unknown. The objectives of the present study were (1) to determine the dose of clopidogrel needed in infants and young children to achieve a mean 30% to 50% inhibition of 5-μmol/L ADP–induced platelet aggregation (ie, inhibition similar to that observed with 75 mg in adults) and (2) to assess the safety and tolerability of clopidogrel in infants and young children.

Methods and Results— We performed a prospective, multicenter, randomized, placebo-controlled trial evaluating the pharmacodynamics of clopidogrel in children (0 to 24 months) with a cardiac condition at risk for arterial thrombosis. Patients were randomized to clopidogrel versus placebo in a 3:1 ratio in 4 sequential groups (0.01, 0.10, 0.20, and 0.15 mg/kg) for 7 abd 28 days. Platelet aggregation was assessed at baseline and steady state by light-transmission aggregometry. Of 116 patients enrolled, 92 (50% neonates, 50% infants/toddlers) were randomized, and 73 completed the study. A total of 79% of the randomized and treated patients were taking aspirin.

Compared with placebo, clopidogrel 0.20 mg · kg−1 · d−1 resulted in a mean 49.3% (95% confidence interval 25.7% to 72.8%) inhibition of the maximum extent of platelet aggregation and a mean 43.9% (95% confidence interval 18.6% to 69.2%) inhibition of the rate of platelet aggregation. There was marked interpatient variability in the degree of platelet aggregation inhibition within each treatment-dose group and age group. No serious bleeding events occurred.

Conclusions— Clopidogrel 0.20 mg/kg/day in children 0 to 24 months of age achieves a platelet inhibition level similar to that in adults taking 75 mg/d. Clopidogrel is well tolerated in infants and young children at this dose.

Diuretics - High dose vs. Low dose (Adult study)

Diuretic Strategies in Patients with Acute Decompensated Heart Failure
G. Michael Felker, M.D., et al. for the NHLBI Heart Failure Clinical Research Network
N Engl J Med 2011; 364:797-805
March 3, 2011

Background
Loop diuretics are an essential component of therapy for patients with acute decompensated heart failure, but there are few prospective data to guide their use.

Methods
In a prospective, double-blind, randomized trial, we assigned 308 patients with acute decompensated heart failure to receive furosemide administered intravenously by means of either a bolus every 12 hours or continuous infusion and at either a low dose (equivalent to the patient's previous oral dose) or a high dose (2.5 times the previous oral dose). The protocol allowed specified dose adjustments after 48 hours. The coprimary end points were patients' global assessment of symptoms, quantified as the area under the curve (AUC) of the score on a visual-analogue scale over the course of 72 hours, and the change in the serum creatinine level from baseline to 72 hours.

Results
In the comparison of bolus with continuous infusion, there was no significant difference in patients' global assessment of symptoms (mean AUC, 4236±1440 and 4373±1404, respectively; P=0.47) or in the mean change in the creatinine level (0.05±0.3 mg per deciliter [4.4±26.5 μmol per liter] and 0.07±0.3 mg per deciliter [6.2±26.5 μmol per liter], respectively; P=0.45). In the comparison of the high-dose strategy with the low-dose strategy, there was a nonsignificant trend toward greater improvement in patients' global assessment of symptoms in the high-dose group (mean AUC, 4430±1401 vs. 4171±1436; P=0.06). There was no significant difference between these groups in the mean change in the creatinine level (0.08±0.3 mg per deciliter [7.1±26.5 μmol per liter] with the high-dose strategy and 0.04±0.3 mg per deciliter [3.5±26.5 μmol per liter] with the low-dose strategy, P=0.21). The high-dose strategy was associated with greater diuresis and more favorable outcomes in some secondary measures but also with transient worsening of renal function.

Conclusions
Among patients with acute decompensated heart failure, there were no significant differences in patients' global assessment of symptoms or in the change in renal function when diuretic therapy was administered by bolus as compared with continuous infusion or at a high dose as compared with a low dose. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT00577135.)

Editorial on the above article:
Comparative Effectiveness of Diuretic Regimens
Gregg C. Fonarow, M.D.
N Engl J Med 2011; 364:877-878
March 3, 2011

Acute decompensated heart failure is associated with substantial morbidity, mortality, and health care expenditures.1 Most patients present with symptoms related to fluid overload, which may be complicated by concomitant renal dysfunction.2 Treating the signs and symptoms of heart failure while preserving or improving renal function is a crucial therapeutic goal.
For more than five decades, the administration of intravenous loop diuretics has been the mainstay of therapy to reduce congestion, decrease ventricular filling pressures, and improve symptoms of heart failure, with such therapy becoming an empirically accepted standard of care for this condition.1,3,4 However, there is little evidence . . .

Hypertension with Dexmedetomidine

Genetic Variations in the α2A-Adrenoreceptor Are Associated with Blood Pressure Response to the Agonist Dexmedetomidine
Daniel Kurnik et al.

CIRC GENETICS.110.957662 Published online before print February 15, 2011​

Background—α2A-Adrenoceptors (α2AA-ARs) have important roles in sympathetic cardiovascular regulation. Variants of ADRA2A affect gene transcription and expression and are associated with insulin release and risk for type 2 diabetes. We examined whether ADRA2A variants are also associated with cardiovascular responses to the selective α2-AR-agonist, dexmedetomidine.

Methods and Results—73 healthy subjects participated in a placebo-controlled single-blind study. After 3 infusions of placebo, subjects received 3 incremental infusions of dexmedetomidine (cumulative dose, 0.4 mcg/kg). Primary outcomes were changes in systolic blood pressure (SBP) and plasma norepinephrine concentrations, measured as difference of the area-under-the-curve during placebo and dexmedetomidine infusions (ΔAUC). We used multiple linear regression analysis to examine the associations between 9 ADRA2A tagging variants and 5 inferred haplotypes and ΔAUC after adjustment for covariates. Homozygous carriers of rs553668, and the corresponding haplotype 4, previously associated with increased α2A-AR expression, had a 2.2-fold greater decrease in AUCSBP after dexmedetomidine (adjusted P=0.006); similarly, the maximum decrease in SBP was 24.7±8.1 mmHg compared to 13.6±5.9 mmHg in carriers of the wildtype allele (P=0.007). Carriers of haplotype 3, previously associated with reduced α2A-AR expression, had a 44% smaller decrease in AUCSBP (P=0.013). Haplotype information significantly improved the model predicting the decrease in SBP (P<0.001). There were similar but non-significant trends for diastolic blood pressure and heart rate. Genotypes were not significantly associated with norepinephrine responses.

Conclusions—Common ADRA2A variants are associated with the hypotensive response to dexmedetomidine. Effects of specific variants/haplotypes in vivo are compatible with their known effects on gene expression in vitro.

Diuretics: Sequential blockade (Diuril-Lasix) "misconception"

JACC 2010;56:1527-34

Combination of Loop Diuretics With Thiazide-Type Diuretics in Heart Failure

Jacob C. Jentzer, MD,Tracy A. DeWald, RD, PharmD, BCPS andAdrian F. Hernandez, MD

Volume overload is an important clinical target in heart failure management, typically addressed using loop diuretics. An important and challenging subset of heart failure patients exhibit fluid overload despite significant doses of loop diuretics. One approach to overcome loop diuretic resistance is the addition of a thiazide-typediuretic to produce diuretic synergy via "sequential nephron blockade," first described more than 40 years ago. Although potentially able to induce diuresis in patients otherwise resistant to high doses of loop diuretics, this strategy has not been subjected to large-scale clinical trials to establish safety and clinical efficacy. We summarize the existing literature evaluating the combination of loop and thiazide diuretics in patients with heart failure in order to describe the possible benefits and hazards associated with this therapy. Combinationdiuretic therapy using any of several thiazide-type diuretics can more than double daily urine sodium excretion to induce weight loss and edema resolution, at the risk of inducing severe hypokalemia in addition to hyponatremia, hypotension, and worsening renal function. We provide considerations about prudent use of this therapy and review potential misconceptions about this long-used diuretic approach. Finally, we seek to highlight the need for pragmatic clinical trials for this commonly used therapy.

Warfarin - Genotyping

Warfarin genotyping reduces hospitalization rates. Results from MM-WES (Medco-Mayo Warfarin Effectiveness Study).
Robert S. Epstein, et al. JACC 2010;55(25):2804-12.
Article
Editorial comments

Two genes have been shown in past decade to influence warfarin dosing.
One gene, CYP2C9 determines the activity of hepatic isoenzyme cytochrome P450 2C9 that plays a role in converting S-war-farin to its inactive form.
Second gene, VKORC1 - determines the activity of Vit K epoxide reductase that produces the active form of Vit K that is necessary for clotting.

CYP 2C9 & NKORC1 polymorphisms account for > 1/3rd of variations associated with variations in warfarin dosage. Warfarin sensitivity genotyping involves a test that simultaneously tests for allelic variation in both genes.

Genetic testing is not widely adopted due to lack of studies demonstrating the utility of these tests. This is the first national study on this.