Context Despite decades of accumulated observational evidence, the balance of risks and benefits for hormone use in healthy postmenopausal women remains uncertain Objective To assess the major health benefits and risks of the most commonly used combined hormone preparation in the United States Design Estrogen plus progestin component of the Women's Health Initiative, a randomized controlled primary prevention trial (planned duration, 85 years) in which 16608 postmenopausal women aged 50-79 years with an intact uterus at baseline were recruited by 40 US clinical centers in 1993-1998 Interventions Participants received conjugated equine estrogens, 0625 mg/d, plus medroxyprogesterone acetate, 25 mg/d, in 1 tablet (n = 8506) or placebo (n = 8102) Main outcomes measures The primary outcome was coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome A global index summarizing the balance of risks and benefits included the 2 primary outcomes plus stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, and death due to other causes Results On May 31, 2002, after a mean of 52 years of follow-up, the data and safety monitoring board recommended stopping the trial of estrogen plus progestin vs placebo because the test statistic for invasive breast cancer exceeded the stopping boundary for this adverse effect and the global index statistic supported risks exceeding benefits This report includes data on the major clinical outcomes through April 30, 2002 Estimated hazard ratios (HRs) (nominal 95% confidence intervals [CIs]) were as follows: CHD, 129 (102-163) with 286 cases; breast cancer, 126 (100-159) with 290 cases; stroke, 141 (107-185) with 212 cases; PE, 213 (139-325) with 101 cases; colorectal cancer, 063 (043-092) with 112 cases; endometrial cancer, 083 (047-147) with 47 cases; hip fracture, 066 (045-098) with 106 cases; and death due to other causes, 092 (074-114) with 331 cases Corresponding HRs (nominal 95% CIs) for composite outcomes were 122 (109-136) for total cardiovascular disease (arterial and venous disease), 103 (090-117) for total cancer, 076 (069-085) for combined fractures, 098 (082-118) for total mortality, and 115 (103-128) for the global index Absolute excess risks per 10 000 person-years attributable to estrogen plus progestin were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while absolute risk reductions per 10 000 person-years were 6 fewer colorectal cancers and 5 fewer hip fractures The absolute excess risk of events included in the global index was 19 per 10 000 person-years Conclusions Overall health risks exceeded benefits from use of combined estrogen plus progestin for an average 52-year follow-up among healthy postmenopausal US women All-cause mortality was not affected during the trial The risk-benefit profile found in this trial is not consistent with the requirements for a viable intervention for primary prevention of chronic diseases, and the results indicate that this regimen should not be initiated or continued for primary prevention of CHD

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Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women's Health Initiative randomized controlled trial

2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC.

ACC/AHA
: American College of Cardiology/American Heart Association
ACCF/AHA
: American College of Cardiology Foundation/American Heart Association
ACE
: angiotensin-converting enzyme
ACEI
: angiotensin-converting enzyme inhibitor
ACS
: acute coronary syndrome
AF
: atrial fibrillation

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2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure

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Authors/Task Force Members: John J.V. McMurray (Chairperson) (UK)*, Stamatis Adamopoulos (Greece), Stefan D. Anker (Germany), Angelo Auricchio (Switzerland), Michael Böhm (Germany), Kenneth Dickstein (Norway), Volkmar Falk (Switzerland), Gerasimos Filippatos (Greece), Cândida Fonseca (Portugal), Miguel Angel Gomez-Sanchez (Spain), Tiny Jaarsma (Sweden), Lars Køber (Denmark), Gregory Y.H. Lip (UK), Aldo Pietro Maggioni (Italy), Alexander Parkhomenko (Ukraine), Burkert M. Pieske (Austria), Bogdan A. Popescu (Romania), Per K. Rønnevik (Norway), Frans H. Rutten (The Netherlands), Juerg Schwitter (Switzerland), Petar Seferovic (Serbia), Janina Stepinska (Poland), Pedro T. Trindade (Switzerland), Adriaan A. Voors (The Netherlands), Faiez Zannad (France), Andreas Zeiher (Germany).

ESC Guidelines for the Diagnosis And Treatment of Acute And Chronic Heart Failure 2008

Objective: To evaluate the association between use of hormone replacement therapy and the risk of idiopathic venous thromboembolism. Design: Population based case-control study. Setting: Population enrolled in the General Practice Research Database, United Kingdom. Subjects: A cohort of 347 253 women aged 50 to 79 without major risk factors for venous thromboembolism was identified. Cases were 292 women admitted to hospital for a first episode of pulmonary embolism or deep venous thrombosis; 10 000 controls were randomly selected from the source cohort. Main outcome measures: Adjusted relative risks estimated from unconditional logistic regression. Results: The adjusted odds ratio of venous thromboembolism for current use of hormone replacement therapy compared with non-users was 2.1 (95% confidence interval 1.4 to 3.2). This increased risk was restricted to first year users, with odds ratios of 4.6 (2.5 to 8.4) during the first six months and 3.0 (1.4 to 6.5) 6-12 months after starting treatment. No major risk differences were observed between users of low and high doses of oestrogens, unopposed and opposed treatment, and oral and transdermal preparations. The risk of idiopathic venous thromboembolism among non-users of replacement therapy was estimated to be 1.3 per 10 000 women per year. Among current users, idiopathic venous thromboembolism occurs at two to three times the rate in non-users, resulting in one to two additional cases per 10 000 women per year. Conclusions: Current use of hormone replacement therapy was associated with a higher risk of venous thromboembolism, although the risk seemed to be restricted to the first year of use.

Hormone replacement therapy and risk of venous thromboembolism: population based case-control study

Nonsteroidal anti-inflammatory drugs and risk of ARF in the general population.

Background: The risk of upper gastrointestinal (GI) complications associated with the use of NSAIDs is a serious public health concern. The risk varies between individual NSAIDs; however, there is little information on the risk associated with some NSAIDs and on the impact of risk factors. These data are necessary to evaluate the benefit-risk of individual NSAIDs for clinical and health policy decision making. Within the European Community’s Seventh Framework Programme, the Safety Of non-Steroidal anti-inflammatory drugs (NSAIDs) [SOS] project aims to develop decision models for regulatory and clinical use of individual NSAIDs according to their GI and cardiovascular safety. Objective: The aim of this study was to conduct a systematic review and metaanalysis of observational studies to provide summary relative risks (RR) of upper GI complications (UGIC) associated with the use of individual NSAIDs, including selective cyclooxygenase-2 inhibitors. Methods: We used the MEDLINE database to identify cohort and case-control studies published between 1 January 1980 and 31 May 2011, providing adjusted effect estimates for UGIC comparing individual NSAIDs with non-use of NSAIDs. We estimated pooled RR and 95% CIs of UGIC for individual NSAIDs overall and by dose using fixed- and random-effects methods. Subgroup analyses were conducted to evaluate methodological and clinical heterogeneity between studies. Results: A total of 2984 articles were identified and 59 were selected for data

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Individual NSAIDs and Upper Gastrointestinal Complications: A Systematic Review and Meta-Analysis of Observational Studies (the SOS Project)

Background: The risk of upper gastrointestinal (GI) complications associated with the use of NSAIDs is a serious public health concern. The risk varies between individual NSAIDs; however, there is little information on the risk associated with some NSAIDs and on the impact of risk factors. These data are necessary to evaluate the benefit-risk of individual NSAIDs for clinical and health policy decision making. Within the European Community’s Seventh Framework Programme, the Safety Of non-Steroidal anti-inflammatory drugs (NSAIDs) [SOS] project aims to develop decision models for regulatory and clinical use of individual NSAIDs according to their GI and cardiovascular safety. Objective: The aim of this study was to conduct a systematic review and meta-analysis of observational studies to provide summary relative risks (RR) of upper GI complications (UGIC) associated with the use of individual NSAIDs, including selective cyclooxygenase-2 inhibitors. Methods: We used the MEDLINE database to identify cohort and case-control studies published between 1 January 1980 and 31 May 2011, providing adjusted effect estimates for UGIC comparing individual NSAIDs with non-use of NSAIDs. We estimated pooled RR and 95% CIs of UGIC for individual NSAIDs overall and by dose using fixed- and random-effects methods. Subgroup analyses were conducted to evaluate methodological and clinical heterogeneity between studies. Results: A total of 2984 articles were identified and 59 were selected for data abstraction. After review of the abstracted information, 28 studies met the meta-analysis inclusion criteria. Pooled RR ranged from 1.43 (95% CI 0.65, 3.15) for aceclofenac to 18.45 (95% CI 10.99, 30.97) for azapropazone. RR was less than 2 for aceclofenac, celecoxib (RR 1.45; 95% CI 1.17, 1.81) and ibuprofen (RR 1.84; 95% CI 1.54, 2.20); 2 to less than 4 for rofecoxib (RR 2.32; 95% CI 1.89, 2.86), sulindac (RR 2.89; 95% CI 1.90, 4.42), diclofenac (RR 3.34; 95% CI 2.79, 3.99), meloxicam (RR 3.47; 95% CI 2.19, 5.50), nimesulide (RR 3.83; 95% CI 3.20, 4.60) and ketoprofen (RR 3.92; 95% CI 2.70, 5.69); 4–5 for tenoxicam (RR 4.10; 95% CI 2.16, 7.79), naproxen (RR 4.10; 95% CI 3.22, 5.23), indometacin (RR 4.14; 95% CI 2.91, 5.90) and diflunisal (RR 4.37; 95% CI 1.07, 17.81); and greater than 5 for piroxicam (RR 7.43; 95% CI 5.19, 10.63), ketorolac (RR 11.50; 95% CI 5.56, 23.78) and azapropazone. RRs for the use of high daily doses of NSAIDs versus non-use were 2-3 times higher than those associated with low daily doses. Conclusions: We confirmed variability in the risk of UGIC among individual NSAIDs as used in clinical practice. Factors influencing findings across studies (e.g. definition and validation of UGIC, exposure assessment, analysis of new vs prevalent users) and the scarce data on the effect of dose and duration of use of NSAIDs and on concurrent use of other medications need to be addressed in future studies, including SOS.

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Individual NSAIDs and Upper Gastrointestinal Complications

Purpose

To validate ICD 9 codes with a high positive predictive value (PPV) for incident strokes. The study population consisted of Tennessee Medicaid enrollees aged from 50 to 84 years.



Methods

We identified all patients who were hospitalized with a discharge diagnosis of stroke between 1999 and 2003 using highly specific codes (ischemic stroke ICD 9-CM codes 433.x1, 434 [excluding 434.x0], or 436; intracerebral hemorrhage [431]; and subarachnoid hemorrhage [430]). We reviewed medical records of a systematic sample of 250 cohort members. We randomly selected 10–30 eligible records for review from hospitals with at least 10 stroke hospitalizations.



Results

We reviewed 231 charts (93% of total sampled), and 205 (89%) met study criteria for new outpatient stroke. Of the 205 confirmed new outpatient strokes, 196 had stroke listed as the primary discharge diagnosis (PPV = 96%). However, 46 (23%) of the 196 patients identified by the primary diagnosis also had a remote stroke history (recurrent stroke not incident). Thus the PPV of the primary discharge diagnosis for identifying incident stroke decreased to 74%. When we applied an algorithm that restricted our population to those with stroke as the primary diagnosis and excluded patients with any prior outpatient diagnosis of stroke, we identified incident stroke events with more precision (PPV = 80%).



Conclusion

The PPV of incident strokes was 80% using our strategy of primary discharge diagnosis and excluding prior outpatient diagnoses of stroke. Although an unknown percentage of incident strokes are missed, this group of proven incident stroke patients can be used for etiologic studies of medication exposures. Copyright © 2007 John Wiley & Sons, Ltd.

Jordi Castellsague

Papers

Hormone replacement therapy and risk of venous thromboembolism: population based case-control study

Nonsteroidal anti-inflammatory drugs and risk of ARF in the general population.

Individual NSAIDs and Upper Gastrointestinal Complications: A Systematic Review and Meta-Analysis of Observational Studies (the SOS Project)

Individual NSAIDs and Upper Gastrointestinal Complications

Validation of ICD-9 codes with a high positive predictive value for incident strokes resulting in hospitalization using Medicaid health data.