Niels Gadsbøll

Risk of Bleeding With Single, Dual, or Triple Therapy With Warfarin, Aspirin, and Clopidogrel in Patients With Atrial Fibrillation

BACKGROUND Patients with atrial fibrillation (AF) often require anticoagulation and platelet inhibition, but data are limited on the bleeding risk of combination therapy. METHODS We performed a cohort study using nationwide registries to identify all Danish patients surviving first-time hospitalization for AF between January 1, 1997, and December 31, 2006, and their posthospital therapy of warfarin, aspirin, clopidogrel, and combinations of these drugs. Cox proportional hazards models were used to estimate risks of nonfatal and fatal bleeding. RESULTS A total of 82,854 of 118,606 patients (69.9%) surviving AF hospitalization had at least 1 prescription filled for warfarin, aspirin, or clopidogrel after discharge. During mean (SD) follow-up of 3.3 (2.6) years, 13,573 patients (11.4%) experienced a nonfatal or fatal bleeding. The crude incidence rate for bleeding was highest for dual clopidogrel and warfarin therapy (13.9% per patient-year) and triple therapy (15.7% per patient-year). Using warfarin monotherapy as a reference, the hazard ratio (95% confidence interval) for the combined end point was 0.93 (0.88-0.98) for aspirin, 1.06 (0.87-1.29) for clopidogrel, 1.66 (1.34-2.04) for aspirin-clopidogrel, 1.83 (1.72-1.96) for warfarin-aspirin, 3.08 (2.32-3.91) for warfarin-clopidogrel, and 3.70 (2.89-4.76) for warfarin-aspirin-clopidogrel. CONCLUSIONS In patients with AF, all combinations of warfarin, aspirin, and clopidogrel are associated with increased risk of nonfatal and fatal bleeding. Dual warfarin and clopidogrel therapy and triple therapy carried a more than 3-fold higher risk than did warfarin monotherapy.

Rising rates of hospital admissions for atrial fibrillation.

Background: Atrial fibrillation is a common arrhythmia associated with excess morbidity and mortality. We studied temporal changes in hospital admission rates for atrial fibrillation using data from a prospective population-based cohort study spanning 2 decades (the Copenhagen City Heart Study). Methods: The study included baseline data collected in 1981 through 1983 on 10,955 persons age 40 to 79 years and baseline data collected in 1991 through 1994 on 7212 persons age 40 to 79 years. We used hospital diagnosis data from the Danish National Hospital Discharge Register to determine the rate of first hospital admission for atrial fibrillation during 7 years following each of the 2 baseline data collecting periods. Changes in admission rates were analyzed using Cox proportional hazard models. Results: During the 2 7-year periods, 379 subjects were admitted with a hospital diagnosis of atrial fibrillation. The rate of hospital admissions for atrial fibrillation increased among both men and women from the first to the second period (relative risk = 1.6; 95% confidence interval = 1.3–1.9 [adjusted for age, sex, prior myocardial infarction, arterial hypertension, diabetes mellitus, electrocardiographic left ventricular hypertrophy, decreased lung function, smoking, height, and weight]). Conclusion: During the latest 10 to 20 years, there has been a 60% increase in hospital admissions for atrial fibrillation independent of changes in known risk factors. This increase could result from changes in admission threshold or coding practices, or it could reflect a genuine increase in the population incidence of atrial fibrillation.

Increased mortality and cardiovascular morbidity associated with use of nonsteroidal anti-inflammatory drugs in chronic heart failure.

BACKGROUND Accumulating evidence indicates increased cardiovascular risk associated with nonsteroidal anti-inflammatory drug (NSAID) use, in particular in patients with established cardiovascular disease. We studied the risk of death and hospitalization because of acute myocardial infarction and heart failure (HF) associated with use of NSAIDs in an unselected cohort of patients with HF. METHODS We identified 107,092 patients surviving their first hospitalization because of HF between January 1, 1995, and December 31, 2004, and their subsequent use of NSAIDs from individual-level linkage of nationwide registries of hospitalization and drug dispensing by pharmacies in Denmark. Data analysis was performed using Cox proportional hazard models adjusted for age, sex, calendar year, comorbidity, medical treatment, and severity of disease, and propensity-based risk-stratified models and case-crossover models. RESULTS A total of 36,354 patients (33.9%) claimed at least 1 prescription of an NSAID after discharge; 60,974 (56.9%) died, and 8970 (8.4%) and 39,984 (37.5%) were hospitalized with myocardial infarction or HF, respectively. The hazard ratio (95% confidence interval) for death was 1.70 (1.58-1.82), 1.75 (1.63-1.88), 1.31 (1.25-1.37), 2.08 (1.95-2.21), 1.22 (1.07-1.39), and 1.28 (1.21-1.35) for rofecoxib, celecoxib, ibuprofen, diclofenac, naproxen, and other NSAIDs, respectively. Furthermore, there was a dose-dependent increase in risk of death and increased risk of hospitalization because of myocardial infarction and HF. Propensity-based risk-stratified analysis and case-crossover models yielded similar results. CONCLUSIONS NSAIDs are frequently used in patients with HF and are associated with increased risk of death and cardiovascular morbidity. Inasmuch as even commonly used NSAIDs exerted increased risk, the balance between risk and benefit requires careful consideration when any NSAID is given to patients with HF.

Persistent Use of Evidence-Based Pharmacotherapy in Heart Failure Is Associated With Improved Outcomes

Background— Undertreatment with recommended pharmacotherapy is a common problem in heart failure and may influence prognosis. We studied initiation and persistence of evidence-based pharmacotherapy in 107 092 patients discharged after first hospitalization for heart failure in Denmark from 1995 to 2004. Methods and Results— Prescriptions of dispensed medication and mortality were identified by an individual-level linkage of nationwide registers. Inclusion was irrespective of left ventricular function. Treatment with renin-angiotensin inhibitors (eg, angiotensin-converting enzyme inhibitors and angiotensin-2 receptor blockers), &bgr;-blockers, spironolactone, and statins was initiated in 43%, 27%, 19%, and 19% of patients, respectively. Patients who did not initiate treatment within 90 days of discharge had a low probability of later treatment initiation. Treatment dosages were in general only 50% of target dosages and were not increased during long-term treatment. Short breaks in therapy were common, but most patients reinitiated treatment. Five years after initiation of treatment, 79% patients were still on renin-angiotensin inhibitors, 65% on &bgr;-blockers, 56% on spironolactone, and 83% on statins. Notably, multiple drug treatment and increased severity of heart failure was associated with persistence of treatment. Nonpersistence with renin-angiotensin inhibitors, &bgr;-blockers, and statins was associated with increased mortality with hazard ratios for death of 1.37 (95% CI, 1.31 to 1.42), 1.25 (95% CI, 1.19 to 1.32), 1.88 (95% CI, 1.67 to 2.12), respectively. Conclusions— Persistence of treatment was high once medication was started, but treatment dosages were below recommended dosages. Increased severity of heart failure or increased number of concomitant medications did not worsen persistence, but nonpersistence identified a high-risk population of patients who required special attention. A focused effort on early treatment initiation, appropriate dosages, and persistence with the regimen is likely to provide long-term benefit.

Are right and left ventricular ejection fractions equal? Ejection fractions in normal subjects and in patients with first acute myocardial infarction.

Right and left ventricular ejection fractions (RVEF and LVEF) were determined by radionuclide imaging in 37 normal subjects and 37 patients by means of (1) the traditional way of calculating ejection fraction from first-pass time-activity curves of each ventricle generated from a single fixed ventricular region of interest, (2) dual first-pass time-activity curves generated from the end-diastolic and end-systolic regions, respectively, and (3) the multigated equilibrium method, also applying separate regions in end-diastole and end-systole for each ventricle. Values for RVEF measured by method 2 were significantly higher than values obtained by methods 1 and 3. In normal subjects, the values for RVEF measured by method 2 were equal to the values for LVEF determined by either this method or the equilibrium technique. Methods 1 and 3 had a tendency for underestimation of RVEF, probably because of inclusion of right atrial activity into the right ventricular region of interest. Methods 2 and 3 were applied to measure RVEF and LVEF, respectively, in 153 patients in the second week after first acute myocardial infarction. Among these, 25% had normal ejection fractions, 47% had a decrease in only LVEF, 8% a decrease in only RVEF, and 20% a decrease in both RVEF and LVEF.

Increased short-term risk of thrombo-embolism or death after interruption of warfarin treatment in patients with atrial fibrillation

AIMS It is presently unknown whether patients with atrial fibrillation (AF) are at increased risk of thrombo-embolic adverse events after interruption of warfarin treatment. The purpose of this study was to assess the risk and timing of thrombo-embolism after warfarin treatment interruption. METHODS AND RESULTS A retrospective, nationwide cohort study of all patients in Denmark treated with warfarin after a first hospitalization with AF in the period 1997-2008. Incidence rate ratios (IRRs) of thrombo-embolic events and all-cause mortality were calculated using the Poisson regression analyses. In total, 48 989 AF patients receiving warfarin treatment were included. Of these, 35 396 patients had at least one episode of warfarin treatment interruption. In all, 8255 deaths or thrombo-embolic events occurred during treatment interruption showing an initial clustering of events with 2717, 835, 500, and 427 events occurring during 0-90, 91-180, 181-270, and 271-360 days after treatment interruption, respectively. Correspondingly, the crude incidence rates were 31.6, 17.7, 12.3, and 11.4 events per 100 patient-years. In a multivariable analysis, the first 90-day interval of treatment interruption was associated with a markedly higher risk of death or thrombo-embolism (IRR 2.5; 95% confidence interval 2.3-2.8) vs. the interval of 271-360 days. CONCLUSION In patients with AF, an interruption of warfarin treatment is associated with a significantly increased short-term risk of death or thrombo-embolic events within the first 90 days of treatment interruption.

Late Ventricular Dilatation in Survivors of Acute Myocardial Infarction

The purpose of this study was to assess the natural course of left ventricular (LV) volumes in the convalescent phase of acute myocardial infarction (AMI). Fifty-seven patients were examined 2 weeks and approximately 1 year after AMI by a radionuclide method allowing determination of absolute LV volumes. After 1 year the patients had fewer clinical and radiologic signs of heart failure, but median end-diastolic volume index had increased from 92 to 112 ml/m2 (p less than 0.001), median end-systolic volume index from 51 to 65 ml/m2 (p less than 0.001) and median stroke volume index from 39 to 47 ml/m2 (p less than 0.001). Patients with first anterior infarcts had significantly greater increases in end-diastolic volume index, end-systolic volume index and stroke volume index than patients with first inferoposterior infarcts. The increase in LV volumes was significantly greater in patients with clinical manifestations of heart failure than in those without these signs. Notably, changes in LV size had an unpredictable effect on LV ejection fraction.

Temporal decline in the prognostic impact of a recurrent acute myocardial infarction 1985 to 2002

Objective: To investigate trends in case-fatality and prognostic impact from recurrent acute myocardial infarction (re-AMI) during 1985–2002. Design: Retrospective cohort study using nationwide administrative data from Denmark. Settings: National registries on hospital admissions and causes of death were linked to identify patients with first AMI, re-AMI and subsequent prognosis. Patients: Patients ⩾30 years old with a discharge diagnosis of AMI during 1985–2002 were tracked for first hospital admission for re-AMI 1 year after discharge. Main outcome measures: One-year case-fatality. Results: 166 472 patients were identified with a first AMI; 14 123 developed re-AMI. One-year crude case-fatality from first AMI/re-AMI was 39% versus 43% in 1985–1989 and 25% versus 29% in 2000–2002, respectively. In 1985–89, 35 795 patients survived to discharge (71%); of these 2.5% experienced reinfarction within 30 days (early reinfarction) and an additional 9.0% reinfarction within days 31–365 (late re-AMI). Re-AMI carried a poor prognosis in 1985–1989 compared to no re-AMI with age- and sex-adjusted relative risk of 1-year case-fatality of 7.5 (95% CI: 6.9 to 8.5) from early re-AMI and 11.7 (95% CI: 11.0 to 12.4) from late re-AMI. In 2000–2002, 23 552 patients (86%) survived to discharge; 4.4% had early re-AMI and 6.6% late re-AMI. Adjusted relative risk of 1-year case-fatality had declined to 2.1 (95% CI: 1.9 to 2.5) from early re-AMI and 5.6 (95% CI: 5.1 to 6.2) from late re-AMI compared to patients without reinfarction. Conclusion: Prognosis after AMI has improved substantially during the latest two decades and extends to patients with re-AMI.

Nationwide trends in the prescription of beta-blockers and angiotensin-converting enzyme inhibitors after myocardial infarction in Denmark, 1995–2002

Objectives To study the use of beta-blockers and angiotensin-converting enzyme (ACE) inhibitors after acute myocardial infarction (AMI) in Denmark from 1995 to 2002. Design Information about patients with first AMI aged ≥30 years and the dispensing of beta-blockers and ACE inhibitors from pharmacies within 30 d from discharge was obtained from the National Patient Registry and the Danish Registry of Medicinal Product Statistics. Results Beta-blocker use increased from 38.1% of patients in 1995 to 67.9% in 2002 (OR=3.85, CI: 3.58–4.13). Women, elderly patients and patients taking loop-diuretics and antidiabetic drugs received beta-blockers less frequently, but patients taking loop-diuretics or antidiabetic drugs had the greatest increase. ACE inhibitor use increased from 24.5 to 35.5% (OR=1.86, CI: 1.72–2.01). Women, patients aged <60 years or ≥80 years and patients not taking loop-diuretics received ACE inhibitors less frequently, but patients not taking loop-diuretics had the greatest increase. Conclusions Beta-blocker use increased markedly post-AMI from 1995 to 2002, whereas ACE inhibitor use increased modestly. The results suggested undertreatment of women, elderly patients and people with diabetes.

Impact of diuretic treatment and sodium intake on plasma volume in patients with compensated systolic heart failure.

In patients with heart failure (HF), the use of diuretics may be a double‐edged sword that can alleviate symptoms of congestion, but also result in over‐diuresis and intravascular volume depletion. The purpose of the present study was to examine plasma volume (PV) in HF patients receiving from 0 to 160 mg of furosemide and to investigate whether determination of plasma N‐terminal fragment of pro‐brain natriuretic peptide (NT‐proBNP) concentrations can predict PV‐status.