NEJM journal discussion Dr. J.A. Coetser Dr. J-M

NEJM journal discussion Dr. J.A. Coetser Dr. J-M

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

What we already know 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 Primary outcome 18,3%

Placebo 25,9% (p <0,001) Death (CV cause) 10,8%

13,5% (P=0,01) s-K+ >5,5mmol/L 11,8% (P<0,001)

EMPHASIS-HF 7,2% Eplerenone reduces risk of death and hospitalization in patients with systolic heart failure and mild symptoms Conclusion

Original articles relating to proton pump inhibitors November 25, 2010 Other PPIs Omeprazole What we already know

Cohort study 840 968 babies born alive in Denmark between 1996 and 2008 5082 exposures to PPIs during pregnancy, between 4/52 preconception to end of 1st trimester Major birth defects documented Defined by EUROCAT (European surveillance of congenital anomalies) However, genetic syndromes and chromosomal abnormalities were excluded

Method Results Adjusted odds ratio for prevalence of birth defects with any PPI use = 1,1 (95% CI 0,95 1,34) None of the PPIs were found to be significantly associated with major birth

defects when given during 1st trimester Lanzoprazole only PPI with significantly increased risk if started within 4/52 preconception Results November 11, 2010 Therapies

reducing gastric pH reduces bleeding complications related to antiplatelet drugs Concerns have recently been raised by observational studies regarding the potential for PPIs 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

What we already know 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 COGENT trial ITP

is a disorder characterised by immune destruction and decreased production of platelets Standard 1st line treatment Glucocorticoids IVIG Anti-D immunoglobulin Second line treatment

Azathioprine Rituximab Splenectomy Treatments are short-acting, have severe sideeffects and toxicity What we already know A

thrombopoietin mimetic which stimulates the thrombopoietin receptor Romiplostim 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 >50109 per liter at any scheduled visit) safety outcomes quality of life

Study design 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

Results Worthwhile review articles

Bhatt et al. Clopidogrel with or without Omeprazole in Coronary Artery Disease. N Engl J Med 2010;363:1909-17. Kuter et al. Romiplostim or Standard of Care in Patients with Immune Thrombocytopenia. N Engl J Med 2010;363:1889-99. Pasternak et al. Use of Proton-Pump Inhibitors in Early Pregnancy and the Risk of Birth Defects. N Engl J Med 2010;363:2114-23. Zannad et al. Eplerenone in Patients with Systolic Heart Failure and Mild Symptoms. N Engl J Med 2011;364:11-21.

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