NEJM journal discussion Dr. J.A. Coetser Dr. J-M Nel 24 February 2011

What we already know Activation of mineralocorticoid receptors by aldosterone and corticosteroids have negative effects on the failing heart. Mineralocorticoid antagonism reduces the rate of all-cause mortality and hospitalization in NYHA class III-IV systolic heart failure ◦RALES trial (NYHA class III-IV) ◦EPHESUS trial (systolic dysfunction following MI) Current guidelines recommend adding spironolactone or eplerenone if patient has moderate to severe symptomatic systolic failure

EMPHASIS-HF Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure Aim ◦To assess the effect on clinical outcomes of adding eplerenone to evidence-based treatment for mildly symptomatic (NYHA class II) heart failure Method ◦2737 patients ◦NYHA class II systolic heart failure, with LVEF <35% ◦Randomized to receive along with recommended therapies  Placebo or  Eplerenone up to max 50mg dly po Primary outcome ◦Composite of death from cardiovascular cause and hospitalization for heart failure

EMPHASIS-HF

EMPHASIS-HF Eplerenone group Placebo Primary outcome18,3%25,9% (p <0,001) Death(CV cause)10,8%13,5% (P=0,01) s-K + >5,5mmol/L11,8%7,2% (P<0,001)

Conclusion Eplerenone reduces risk of death and hospitalization in patients with systolic heart failure and mild symptoms

Original articles relating to proton pump inhibitors

November 25, 2010

What we already know Omeprazole Other PPI’s

Method ◦Cohort study ◦ babies born alive in Denmark between 1996 and 2008 ◦5082 exposures to PPI’s during pregnancy, between 4/52 preconception to end of 1 st trimester ◦Major birth defects documented  Defined by EUROCAT (European surveillance of congenital anomalies)  However, genetic syndromes and chromosomal abnormalities were excluded

Results

Results Adjusted odds ratio for prevalence of birth defects with any PPI use = 1,1 (95% CI 0,95 – 1,34) None of the PPI’s were found to be significantly associated with major birth defects when given during 1 st trimester Lanzoprazole only PPI with significantly increased risk if started within 4/52 preconception

November 11, 2010

What we already know Therapies reducing gastric pH reduces bleeding complications related to antiplatelet drugs Concerns have recently been raised by observational studies regarding the potential for PPI’s to blunt the efficacy of clopidogrel ◦In vitro studies showed inhibition of clopidogrel effect on platelets ◦Genetic polymorphisms have been identified that could be associated with decreased response to clopidogrel

COGENT trial Clopidogrel and the Optimization of Gastrointestinal Events Trial ◦International ◦Randomized ◦Double-blinded ◦Double-dummy ◦Placebo-controlled Clopidogrel 75mg + omeprazole 20mg dly vs. clopidogrel 75mg alone

COGENT trial Primary GIT endpoint ◦composite of overt or occult bleeding ◦symptomatic gastroduodenal ulcers or erosion ◦obstruction ◦perforation Primary cardiovascular endpoint composite of death cardiovascular causes nonfatal myocardial infarction Revascularization stroke

COGENT trial Results ◦3761 pts included in analysis ◦GIT events  Clopidogrel + omeprazole = 1,1%  Clopidogrel alone = 2,9% ◦Cardiovascular events  Clopidogrel + omeprazole = 4,9% (hazard ratio 0,99)  Clopidogrel alone = 5,7%

COGENT trial No apparent cardiovascular interaction between clopidogrel and omeprazole, but a clinically meaningful difference in cardiovascular events due to use of a PPI is not ruled out

What we already know ITP is a disorder characterised by immune destruction and decreased production of platelets Standard 1 st line treatment ◦Glucocorticoids ◦IVIG ◦Anti-D immunoglobulin Second line treatment ◦Azathioprine ◦Rituximab ◦Splenectomy Treatments are short-acting, have severe side-effects and toxicity

Romiplostim A thrombopoietin mimetic which stimulates the thrombopoietin receptor

Study design Multicenter Randomized Controlled 52-week Open-label 234 patients with ITP who had not yet undergone splenectomy ◦77 patients receive standard treatment ◦157 patients receive weekly s/c romiplostim

Study design Primary end point ◦incidences of treatment failure and splenectomy Secondary end points ◦rate of a platelet response (a platelet count >50×10 9 per liter at any scheduled visit) ◦safety outcomes ◦quality of life

Results Standard Rx Romiplostim Treatment failure 30% 18% Need for splenectomy 36% 9% Serious adverse events 37% 23% Compared to standard Rx, romiplostim group had ◦Fewer bleeding episodes ◦Less need for transfusion ◦Improved quality of life ◦Slight increased thrombotic rate compared to standard treatment

Worthwhile review articles

Bibliography Bhatt et al. Clopidogrel with or without Omeprazole in Coronary Artery Disease. N Engl J Med 2010;363: Kuter et al. Romiplostim or Standard of Care in Patients with Immune Thrombocytopenia. N Engl J Med 2010;363: Pasternak et al. Use of Proton-Pump Inhibitors in Early Pregnancy and the Risk of Birth Defects. N Engl J Med 2010;363: Zannad et al. Eplerenone in Patients with Systolic Heart Failure and Mild Symptoms. N Engl J Med 2011;364:11-21.