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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
Eplerenone group Placebo
Primary outcome 18,3% 25,9%(p <0,001)
Death (CV cause) 10,8% 13,5%(P=0,01)
s-K+ >5,5mmol/L 11,8% 7,2%(P<0,001)
Conclusion
Eplerenone reduces risk of death and hospitalization in patients with systolic heart failure and mild symptoms
Method
◦Cohort study◦840 968 babies born alive in Denmark between
1996 and 2008◦5082 exposures to PPI’s 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
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 1st trimester
Lanzoprazole only PPI with significantly increased risk if started within 4/52 preconception
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 1st line treatment◦Glucocorticoids◦IVIG◦Anti-D immunoglobulin
Second line treatment◦Azathioprine◦Rituximab◦Splenectomy
Treatments are short-acting, have severe side-effects and toxicity
Study design
MulticenterRandomizedControlled52-weekOpen-label234 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
splenectomySecondary end points
◦rate of a platelet response (a platelet count >50×109 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
Bibliography
Bhatt et al. Clopidogrel with or without Omeprazolein 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 EarlyPregnancy 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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