Late Breakers, I Activity No. 0217-0000-10-098-L01-P Breakers, I.pdf · Frank Romanelli, Pharm.D.,...

Annual Meeting

Late Breakers, I Activity No. 0217-0000-10-098-L01-P Monday, October 18 9:15 a.m.–10:45 a.m. Convention Center: Room 16 Moderator: LeAnn B. Norris, Pharm.D., BCPS, BCOP Clinical Assistant Professor, Department of Clinical Pharmacy and Outcomes Sciences, South Carolina College of Pharmacy, Columbia, South Carolina 9:15 a.m. Cardiovascular Therapeutics

Larisa H. Cavallari, Pharm.D., FCCP, BCPS Associate Professor, Department of Pharmacy Practice, University of Illinois at Chicago, College of Pharmacy, Chicago, Illinois

9:30 a.m. HIV Frank Romanelli, Pharm.D., MPH, BCPS Associate Dean and Associate Professor of Pharmacy, Health Sciences, and Medicine, University of Kentucky, Lexington, Kentucky

9:45 a.m. Ambulatory Care Jill S. Burkiewicz, Pharm.D., BCPS Professor of Pharmacy Practice, Midwestern University–Chicago, College of Pharmacy, Downers Grove, Illinois

10:00 a.m. Critical Care Sara D. Brouse, Pharm.D., BCPS Associate Professor, Texas Tech University of Health Sciences Center, School of Pharmacy, Dallas, Texas; Advanced Practice Pharmacist, Critical Care/Cardiology, VA North Texas Healthcare System, Dallas, Texas

10:15 a.m. Medication Safety Francesca E. Cunningham, Pharm.D. Residency Program Director, Veterans Health Administration and PBM, Center for Medication Safety, Hines, Illinois

10:30 a.m. Psychiatry Tawny B. Smith, Pharm.D. Director, Psychiatric Pharmacy Program, University of Texas, College of Pharmacy, Austin, Texas

Faculty Conflict of Interest Disclosures Sara D. Brouse: no conflicts to disclose Jill S. Burkiewicz: no conflicts to disclose Larisa H. Cavallari: no conflicts to disclose Francesca E. Cunningham: no conflicts to disclose

Annual Meeting

Frank Romanelli: no conflicts to disclose Tawny B. Smith: no conflicts to disclose Learning Objectives

1. Describe a ‘late breaking’ HIV related therapeutic report. 2. Describe limitations in the HIV-Ab response. 3. Define ‘broadly neutralizing Abs (BN Abs).’ 4. Discuss implications of newly discovered BN Abs. 5. Evaluate the clinical literature comparing dopamine versus norepinephrine for shock reversal and

apply the evidence to clinical practice in the ICU. 6. Compare/contrast the adverse effects of dopamine and norepinephrine described in the SOAP-II

trial.

Self-Assessment Questions Self-assessment questions are available online at www.accp.com/am

Frank Romanelli, Pharm.D., MPH, BCPS, AAHIVEAssociate Dean and Associate Professor of Pharmacy

University of Kentucky College of Pharmacy

ACCP FALL MEETING 2010 Late Breaking Papers - HIV

Disclosures

The presenter has no disclosures to reportregarding this presentation.

Objectives

Describe a ‘late breaking’ HIV related therapeutic report.

Describe limitations in the HIV-Ab response. Define ‘broadly neutralizing Abs (BN Abs).’ Discuss implications of newly discovered BN

Abs.

Zhou T, Georgiev I, Wu X, et al. Structuralbasis for broad and potent neutralization of

HIV-1 by antibody VRC01. Science 2010;July 8 (Epub ahead of print).

Neutralizing Antibodies A Step Forward?

Recognition that ‘early’ Abs are particularly ineffective Major impediment in vaccine development Thailand vaccine trial: 30% reduction in infection rates

(p>0.05)/vaccine abandoned Previously ‘broadly neutralizing Abs’ (BN Abs) defined by

ability to negate ~ 40% of HIV strains

Neutralizing Antibodies Structural basis for broad and potent neutralization of HIV-1 by antibody VRC01.

Long recognized that most HIV targeted Abs do not sufficiently neutralize HIV

Focus on critical Ab sites associated with minimal mutations Donor 45 (AA male with long-standing HIV): probed for BN

Abs Three unique BN Abs indentified (VRC01, VRC02, VRC03)

Zhou T, Georgiev I, Wu X, et al. Science 2010;epub:1-8.

Neutralizing Antibodies Structural basis for broad and potent neutralization of HIV-1 by antibody VRC01.

BN Abs active against an unprecedented 90% of HIV strains (notably inclusive of almost all sexually transmitted strains)

VRC01: gp120 specific, avoids confirmationally fluid areas of binding site, not affected by glycan shielding, lacks any auto-reactivity

Source of ‘elite control’?

Zhou T, Georgiev I, Wu X, et al. Science 2010;epub:1-8.

Viral Spiking

Viral Spiking

Credit: NIAID VRC

Challenges

Illicit Ab production in sufficient quantity Illicit Ab response in a timely fashion (within the

window of opportunity)

Clinical Implications

Exogenous administration of Abs (passive immunization) – perinatal transmission?

Ab infused microbicides Vaccine development (active immunization) Gene therapy

HIV Vaccine Research‘Renaissance’

Closing in on HIVs Achilles Heal?

“We are going to be at this a whole before any clinical benefits are

realized.”- Gary Nabel, MD, PhD

LATE BREAKERS, IAMBULATORY CARE

Jill S. Burkiewicz, PharmD, BCPS

Background

National Osteoporosis Foundation:1

Recommends adequate calcium intake of at least 1,200 mg daily, including supplements if necessary, for those age 50 and older

Vitamin D intake of 800-1000 international units

Consider not only impact on bone health, but overall patient health

1. NOF Clinician’s Guide: http://www.nof.org/sites/default/files/pdfs/NOF_ClinicianGuide2009_v7.pdf

Calcium &Vascular Disease:Pros Cardiovascular (CV) risk factors Calcium supplementation ↑ HDL levels1

Small, transient decreases in blood pressure2

Observational studies Inverse relationship between calcium intake and:

Ischemic stroke3

Ischemic heart disease mortality4

1. Reid IR , et al. Am J Med 2002;112:343-7.2. Reid IR, et al. J Clin Endocrinol Metab 2005;90:3824-9.

3. Iso H, et al. Stroke 1999;30:1772-9.4. Bostick RM, et al. Am J Epidemiol 1999:149:151-61.

Calcium & Vascular Disease:Cons Randomized, controlled trial with CV events

pre-specified as secondary endpoints1

Postmenopausal women randomized to calcium supplementation(citrate 1g) or placebo for 5 years Increased risk of MI (RR 2.12, 95% CI 1.01-4.47)

Supplementation acutely ↑serum calcium2

↑ serum calcium levels are a CV risk factor3

Evidence of vascular calcification in patients with renal disease on calcium supplementation4

1. Bolland MJ, et al. BMJ 2008;336:262-6.2. Reid IR Aust N Z J Med 1986:16:193-7.

3. Lind L, et al. J Clin Epidemiol 1997:50:967-73.4. Russo D, et al. Kidney Int 2007;72:1255-61.

Effect of calcium supplements on risk of myocardial infarction and cardiovascular

events: meta-analysis

Bolland MJ, Avenell A, Baron JA, et al. BMJ 2010;341:c3691.

July 29, 2010Bolland MJ, et al. BMJ 2010;341:c3691.

Study Objective & Design

Objective: To investigate whether calcium supplements

increase the risk of cardiovascular disease.

Design: Meta-analysis

Patient-level and trial-level data

Bolland MJ, et al. BMJ 2010;341:c3691.

Methods: Inclusion/Exclusion Criteria Inclusion Criteria:

Randomized, double-blind, placebo-controlled 100 or more participants Duration ≥ 1 year

Elemental calcium ≥ 500 mg/day Baseline mean age > 40 years Female or male participants

Exclusion Criteria: Calcium + Vitamin D v. placebo

Included if vitamin D given to comparator group

Dietary calcium or nutritional supplements only Systemic disease other than osteoporosis


Outcomes: Cardiovascular Events Primary endpoints: Time to 1st myocardial infarction

Time to 1st stroke

Time to 1st cardiovascular event Composite endpoint: myocardial infarction, stroke,

sudden death

Secondary endpoint: All-cause mortality


Search Results


Analysis

Reported patient-level and trial-level data separately

Tests for heterogeneity

Cox proportional hazards model Adjusted for possible covariates associated with CV

outcomes: Age, sex, smoking status, history of DM, DL, HTN or CHD at

baseline

Pre-specified subgroup analyses: Dietary calcium, age, sex, Vitamin D status (≥~20 ng/mL or

<~20 ng/mL), supplement type

Publication bias assessed


Trial Characteristics

15 studies eligible for inclusion 5 studies with patient-level data (n>8,000)

6 studies with only trial-level data (n~3800)

4 studies with trial-level data had no data on CV outcomes

Calcium supplementation ranged from 500 mg to 2 g daily 9/11 studies used doses of 1 g or more

Mean trial duration ~ 4 years

Endpoints typically BMD or fracture

Baseline characteristics: Patient-level analysis

Characteristic Calcium Group Placebo Group

Age, median (IQR) 74.5 years (70-79) 74.6 years (71-79)

Women 76.5% 79.2%

White ethnicity 97.2% 97.7%

Weight, mean (SD) 68.4 kg (14.1) 67.9 kg (13.7)

Dietary calcium, mean (SD) 837 mg/day (377) 831 mg/day (370)

25-OH Vitamin D, mean (SD)

26.4 ng/mL (11.6) 25.7 ng/mL (11.0)

Current smoker 11.0% 10.2%

Hypertension 28.0% 28.4%

Ischemic Heart Disease 8.1% 7.8%

Hyperlipidemia 14.8% 15.4%

Diabetes 7.0% 6.7%

Results

Patient-level data5 studies, n=8151

HR (95% CI)

Trial-level data8 studies, n=6116

HR (95% CI)

MI 1.31 (1.02-1.67)* 1.27 (1.01-1.59)

Stroke 1.20 (0.96-1.50) 1.12 (0.92-1.36)

Composite (MI, stroke,

sudden death)

1.18 (1.00-1.39) 1.12 (0.97-1.30)

Death 1.09 (0.96-1.23) 1.07 (0.95-1.19)

*NNH=69 Bolland MJ, et al. BMJ 2010;341:c3691.

Subgroup Analysis:Dietary Calcium Intake

Dietary calcium intake Myocardial InfarctionHR (95% CI)

Above median (>805 mg/day)

1.85 (1.28-2.67)

Below median (<805 mg/day)

0.98 (0.69-1.38)

Pre-specified subgroup analysis


Author’s conclusions

Treatment of 1000 people with calcium for 5 years: Causes 14 additional myocardial infarctions

Prevents 26 fractures

Supplementation of calcium without coadministered vitamin D is associated with an increased risk of MI

Reconsideration of the role of calcium supplementation in prevention and treatment of osteoporosis is needed


Discussion: Limitations

NOF recommends adequate calcium ANDvitamin D Meta-analysis excluded studies that included

vitamin D

High dietary calcium intake

Trials did not have CV events specified as the primary endpoint

Incomplete data in 15% of participants

Vitamin D & CV Health

In observational studies, Vitamin D deficiency is associated with CV disease and multiple CV risk factors1

Women’s Health Initiative2

Coadministration of calcium 500 mg + vitamin D 200 IU BID had no effect on CHD or stroke risk

Patient population differed from current meta-analysis

1. Reddy Vanga S, et al. Am J Cardiol 2010;106:798-805.2. Hsia J, et al. Circulation 2007;115;846-854.

Clinical Applicability

Assess dietary intake of calcium and vitamin D prior to recommending supplementation

Take an active role in reducing CV risk factors for all patients

Comparison of Dopamine and Norepinephrine in the Treatment of

Shock

De Backer D., et al. N Engl J Med 2010; 362(9): 779-89

Sara Brouse, Pharm.D., FCCP, BCPS, AQ Cardiology

Associate Professor of Pharmacy Practice

Advanced Practice Pharmacist in Critical Care/Cardiology

TTUHSC School of Pharmacy/VA North Texas Medical Center

Surviving Sepsis Campaign 2008Maintain MAP ≥ 65mmHg. (1C)

Norepinephrine or Dopamine centrally administered are the initial vasopressors of choice. (1C)

Epinephrine, phenylephrine, or vasopressin should not be administered as the initial vasopressor in septic shock. (2C)

Vasopressin 0.03 units/min may be subsequently added to norepinephrineDellinger RP, Levy MM, Carlet, JM, et al: Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 2008; 36:296 –327.

+++

++++

++++

Lefkowitz RJ, Hoffman BB, Taylor P. Neurotransmission. In: Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 9th Ed. Eds. Molinoff PB & Ruddon RW. The McGraw Hill Co. Neurotransmission. P120‐121.

++++

++++

++++

++++

0

0

+++

+++

+

++

++++

0

0

0

++ 0

Drug α1 β1 β2 DA

Dopamine (DA) +++ ++++ + ++++

Epinephrine ++++ ++++ +++ 0

Norepinephrine (NE)

++++ ++ 0 0

Isoproterenol 0 ++++ +++ 0

Dobutamine + ++++ ++ 0

Catecholamine Receptor Effects


Sympathetic Nerve Terminal


Dopamine Metabolism

Riker RR et al. JAMA 2009;301(5):489‐99.

Study Group Design/Pop Dose Results

Martin et al. (n=32)

P, R studyHyperdynamic sepsis

DA 2.5‐25 g/kg/min vs NE 0.5‐5 g/kg/min

Effectiveness: DA 10 –25 g/kg/min effective in 31% (5 of 16); NE effective in 93% (15 of 16) ; Survival 17% DA vs 59% NE

Martin et al. (n=97)

P, Obs studyHyperdynamic sepsis

DA 5–15 g/kg/min If no response, DA 16 –25 g/kg/min orNE 0.5–5.0 g/kg/min

Favorable outcome: use of NE‐‐mortality 62% vs. 82% with DA or E or both (p <0.001; RR, 0.68; 95% CI 0.54–0.87)

Sakr et al.(n=3147)

Cohort, MC observational study

N=375 (35%) received DA (dosing variable)

Higher ICU mortality (DA 42.9% vs. NE 35.7%, p=.02) and hospital mortality (49.9% vs. 41.7%, p=.01)

Cochrane Rev 2004

Meta‐analysis NE vs DASeptic

Mortality RR 0.88 (0.57‐1.36)

Povoa et al. (n=897)

Cohort, MC observational studyN=458 septic shock

50.5% received DA and 73% received NE (dosing variable)

NE group had a higher hospital mortality (52% vs. 38.5%, p = 0.002)NE independent risk factor for death

Martin C, et al. Chest 1993;103:1826–1831. Martin C. Crit Care Med. 2000 Aug;28(8):2758‐65. Sakr Y. Crit Care Med. 2006 Mar;34(3):589‐97. Povoa et al. Crit Care Med. 2009 Feb;37(2):410‐6; Mullner M et al. Cochrane Database SystR 2004(3) CD003709

Study ObjectiveTo evaluate whether norepinephrine could reduce death rates in patients with shock more than dopamine

Riker RR et al. JAMA 2009;301(5):489‐99.De Backer D, et al. N Engl J Med 2010;362(9):779‐89.

Methods: Study DesignProspective, Double‐blind, Randomized, Multicenter trial

Study period 28 days

December 2003 to October 2007 in Belgium, Austria, & Spain

1679 Medical/Surgical ICU patients in whom a vasopressor was required for shock syndrome


Inclusion Criteria > 18 years old

Vasopressor agent needed for treatment of shock

“Shock” defined as mean arterial pressure (MAP) less than 70mmHg or systolic blood pressure (SBP) < 100mmHg despite “adequate” fluid resuscitation and signs of tissue hypoperfusion

“Adequate” fluids defined as > 1000mL of crystalloids or 500mL of colloids


Exclusion Criteria

Riker RR et al. JAMA 2009;301(5):489‐99.De Backer D, et al. N Engl J Med 2010;362(9):779‐89. bpm=beats/minute

Less than 18 yrs old

Already received a vasopressor agent for > 4 hours during current shock episode

Serious arrhythmia

Atrial fibrillation with heart rate > 160 bpm

Ventricular tachycardia

Declared braindead

Methods


Dopamine dosed at 2mcg/kg/min & titrated by increments of 2 until max 20mcg/kg/min

Norepinephrine dosed at 0.02mcg/kg/min & titrated to max 0.19mcg/kg/min

Prior vasopressors were discontinued (if received) and transitioned to study drug

Lack of efficacy: open label norepinephrine added

Weaning: open‐label weaned 1st, then study drug

28‐day study period

De Backer D, et al. N Engl J Med 2010;362(9):779‐89.

EndpointsPrimary endpoint

Mortality at 28 days

Secondary endpoints

ICU mortality / Hospital mortality

ICU length of stay

Number of days without need for organ support

Time to hemodynamic stability

Use of dobutamine or other inotropics

Adverse effects


Statistics Estimated 765 patients/ group for 80% power to show 15% mortality difference

Predefined boundaries for early discontinuation Superiority of norepinephrine over dopamine

Superiority of dopamine over norepinephrine

No difference between dopamine or norepinephrine

1o endpoint: unadjusted chi square

2o endpoints: unpaired student’s t‐test or wilcoxon rank‐sum test

Cox proportional‐hazards regression model


Methods: Study Design


Baseline Characteristics DA (n=858) NE (n=821)Age 68 (55‐76) 67 (56‐76)

APACHE II Score / SOFA Score 20 (15‐28)/ 9 (7‐12) 20 (14‐27)/ 9 (6‐12)

Reason for admission, No. (%)Medical 565 (65.9%) 532 (64.8%)

Cause of Shock, No. (%)SepsisCardiogenicHypovolemicOther (intoxication, anaphylactic)

542 (63.2%)135 (15.7%)138 (16.1%)48 (5.9%)

502 (61.1%)145 (17.6%)125 (15.2%)44 (5%)

Open‐Label Norepinephrine, No. (%) 157 (18.3%) 107 (13%)

Mechanical Ventilation, No. (%)Fi02

615 (71.7%)0.59 +/‐0.24

580 (70.6%)0.58 +/‐0.23

Renal Replacement Therapy, No. (%) 63 (7.3%) 61 (7.4%)

Corticosteroids, No. (%) 101 (11.8%) 76 (9.3%)


Results: Primary EndpointTime period

DA NE Odds Ratio (95%CI)

P-value

ICU Mortality

50.2% 45.9% 1.19 (0.98-1.44) 0.07

Hospital Mortality

59.4% 56.6% 1.12 (0.92-1.37) 0.24

28-Day Mortality

52.5% 48.5% 1.17 (0.97-1.42) 0.10

6-Month Mortality

63.8% 62.9% 1.06 (0.86-1.31) 0.71


Results: Secondary EndpointsAchievement of MAP goal of 65 (mean +/‐ SD)

DA 6.3 ± 5.6 hrs vs NE 6 +/‐ 4.9 hrs

Support‐free days through day 28

Vasopressors: DA 11 days vs NE 12.5 days

Mech vent: DA 8.5 days vs NE 9.5 days

ICU not needed: DA 8.1 days vs NE 8.5 days


Results: Standard of Care Fluids

Day 1 DA received more than NE

Hydrocortisone use:

DA 344 (40.1%) vs NE 326 (39.7%)

Drotrecogin alfa use (septic shock):

DA 102 pts (18.8%) vs NE 96 pts (19.1%)

*Open‐label NE: DA 26% vs NE 20%


Results: Safety


ADRs DA, no. (%) NE, no. (%)

Atrial fibrillation 207 (20.5%) 90 (11%)

VT/VF 31 (3.6%) 12 (1.5%)

Skin ischemia 56 (6.5%) 34 (4.1%)

Arterial occlusion 23 (2.7%) 20 (2.4%)

Refractory shock 196 (46%) 155 (41%)

Forest Plot By Type of ShockHazard Ratio (95% CI)

NE Better DA Better

0.5 1.51.0

Type of Shock

HypovolemicCardiogenic

SepticAll Patients

Author’s Conclusions“Although there was no significant difference in the rate of death between patients with shock who were treated with dopamine as the first‐line vasopressor agent and those who were treated with norepinephrine, the use of dopamine was associated with a greater number of adverse events”


DiscussionOne of the largest studies to compare DA and NE head‐to‐head in shock syndromes

50% mortality rate consistent with norm

High external validity including multiple forms of shock syndromes

Early difference in cardiogenic shock mortality due to arrhythmias from dopamine


LimitationsNo mention of standard of care measures used or treatment of underlying cause ? Implemented similarly between groups

Type of shock included

Definition of “adequate administration of fluids” (1 L crystalloid, 500mL colloid)

Definition of resolution of shock ill‐defined

Definition of “Equipotent” vasopressor dose

Open‐label NE allowed (26% DA & 20% NE)


Interpretation: Does NE no longer ‘leave ‘em dead’?Data challenges consensus guideline recommendation for dopamine as 1st‐line

Minimizes perception that norepinephrine causes excessive harmful organ vasoconstriction

Implications for treatment of cardiogenic shock

Guideline change may be warranted

Consistent with SOAP 1 study

Implications for procurement & administration

De Backer D, et al. N Engl J Med 2010;362(9):779‐89.

QUESTIONS?

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