Treatment of Type 2 Diabetes and Outcomes in Patients With Heart Failure: A Nested Case–Control Study From the U.K. General Practice Research Database

OBJECTIVE - Diabetes and heart failure commonly coexist, and prior studies have suggested better outcomes with met formin than other antidiabetic agents. We designed this study to determine whether this association reflects a beneficial effect of metformin or a harmful effect of other agents. RESEARCH DESIGN AND METHODS - We performed a case-control study nested within the U.K. General Practice Research Database cohort in which diagnoses were assigned by each patient's primary care physician. Case subjects were patients 35 years or older, newly diagnosed with both heart failure and diabetes after January 1988, and who died prior to October 2007. Control subjects were matched to case subjects based on age, sex, clinic site, calendar year, and duration of follow-up. Analyses were adjusted for comorbidities, A1C, renal function, and BMI. RESULTS - The duration of concurrent diabetes and heart failure was 2.8 years (SD 2.6) in our 1,633 case subjects and 1,633 control subjects (mean age 78 years, 53% male). Compared with patients who were not exposed to antidiabetic drugs, the current use of metformin monotherapy (adjusted odds ratio 0.65 [0.48-0.87]) or metformin with or without other agents (0.72 [0.59-0.90]) was associated with lower mortality; however, use of other antidiabetic drugs or insulin was not associated with all-cause mortality. Conversely, the use of ACE inhibitors/angiotensin receptor blockers (0.55 [0.45-0.68]) and beta-blockers (0.76 [0.61-0.95]) were associated with reduced mortality. CONCLUSIONS - Our results confirm the benefits of trial-proven anti-failure therapies in patients with diabetes and support the use of metformin-based strategies to lower glucose

Advantages of the nested case-control design in diagnostic research

Abstract Background Despite its benefits, it is uncommon to apply the nested case-control design in diagnostic research. We aim to show advantages of this design for diagnostic accuracy studies. Methods We used data from a full cross-sectional diagnostic study comprising a cohort of 1295 consecutive patients who were selected on their suspicion of having deep vein thrombosis (DVT). We draw nested case-control samples from the full study population with case:control ratios of 1:1, 1:2, 1:3 and 1:4 (per ratio 100 samples were taken). We calculated diagnostic accuracy estimates for two tests that are used to detect DVT in clinical practice. Results Estimates of diagnostic accuracy in the nested case-control samples were very similar to those in the full study population. For example, for each case:control ratio, the positive predictive value of the D-dimer test was 0.30 in the full study population and 0.30 in the nested case-control samples (median of the 100 samples). As expected, variability of the estimates decreased with increasing sample size. Conclusion Our findings support the view that the nested case-control study is a valid and efficient design for diagnostic studies and should also be (re)appraised in current guidelines on diagnostic accuracy research.</p

Survival bias and drug interaction can attenuate cross-sectional case-control comparisons of genes with health outcomes. An example of the kinesin-like protein 6 (KIF6) Trp719Arg polymorphism and coronary heart disease

<p>Abstract</p> <p>Background</p> <p>Case-control studies typically exclude fatal endpoints from the case set, which we hypothesize will substantially underestimate risk if survival is genotype-dependent. The loss of fatal cases is particularly nontrivial for studies of coronary heart disease (CHD) because of significantly reduced survival (34% one-year fatality following a coronary attack). A case in point is the <it>KIF6 </it>Trp719Arg polymorphism (rs20455). Whereas six prospective studies have shown that carriers of the <it>KIF6 </it>Trp719Arg risk allele have 20% to 50% greater CHD risk than non-carriers, several cross-sectional case-control studies failed to show that carrier status is related to CHD. Computer simulations were therefore employed to assess the impact of the loss of fatal events on gene associations in cross-sectional case-control studies, using <it>KIF6 </it>Trp719Arg as an example.</p> <p>Results</p> <p>Ten replicates of 1,000,000 observations each were generated reflecting Canadian demographics. Cardiovascular disease (CVD) risks were assigned by the Framingham equation and events distributed among <it>KIF6 </it>Trp719Arg genotypes according to published prospective studies. Logistic regression analysis was used to estimate odds ratios between <it>KIF6 </it>genotypes. Results were examined for 33%, 41.5%, and 50% fatality rates for incident CVD.</p> <p>In the absence of any difference in percent fatalities between genotypes, the odds ratios (carriers vs. noncarriers) were unaffected by survival bias, otherwise the odds ratios were increasingly attenuated as the disparity between fatality rates increased between genotypes. Additional simulations demonstrated that statin usage, shown in four clinical trials to substantially reduce the excess CHD risk in the <it>KIF6 </it>719Arg variant, should also attenuate the <it>KIF6 </it>719Arg odds ratio in case-control studies.</p> <p>Conclusions</p> <p>These computer simulations show that exclusions of prior CHD fatalities attenuate odds ratios of case-control studies in proportion to the difference in the percent fatalities between genotypes. Disproportionate CHD survival for <it>KIF6 </it>Trip719Arg carriers is suggested by their 50% greater risk for recurrent myocardial infarction. This, and the attenuation of <it>KIF6 </it>719Arg carrier risk with statin use, may explain the genotype's weak association with CHD in cross-sectional case-control studies. The results may be relevant to the underestimation of risk in cross-sectional case-control studies of other genetic CHD-risk factors affecting survival.</p

Anti-arrhythmic drug therapy in implantable cardioverter-defibrillator recipients

Implantable cardioverter-defibrillators (ICDs) have revolutionized the primary and secondary prevention of patients with ventricular arrhythmias. However, the adverse effects of appropriate or inappropriate shocks may require the adjunctive use of anti-arrhythmic drugs (AADs). Beta blockers are the cornerstone of pharmacological primary and secondary prevention of ventricular arrhythmias. In addition to their established efficacy at reducing the incidence of ventricular arrhythmias, beta-blockers are safe with few side effects. Amiodarone is superior to beta blockers and sotalol for the prevention of ventricular arrhythmia recurrence. However, long-term amiodarone use is associated with significant side effects that limit its utility. Sotalol and mexiletine are the main alternatives to amiodarone with a better side effect profile though they are less efficacious at preventing ventricular arrhythmia recurrence. Dofetilide, azimilide and ranolazine are emerging as therapeutic options for secondary prevention; more studies are needed to assess efficacy and safety in comparison to currently used agents. Beta blockers and amiodarone are the mainstay of therapy in patients experiencing electrical storm; their use reduces the frequency of ventricular arrhythmias and ICD intervention as well as affording time until catheter ablation can be considered

Subclinical atrial fibrillation and risk of stroke: Past, present and future

Subclinical atrial fibrillation (SCAF) describes asymptomatic episodes of atrial fibrillation (AF) that are detected by cardiac implantable electronic devices (CIED). The increased utilization of CIEDs renders our understanding of SCAF important to clinical practice. Furthermore, 20% of AF present initially as a stroke event and prolonged cardiac monitoring of stroke patients is likely to uncover a significant prevalence of SCAF. New evidence has shown that implanting cardiac monitors into patients with no history of atrial fibrillation but with risk factors for stroke will yield an incidence of SCAF approaching 30-40% at around three years. Atrial high rate episodes lasting longer than five minutes are likely to represent SCAF. SCAF has been associated with an increased risk of stroke that is particularly significant when episodes of SCAF are greater than 23 h in duration. Longer episodes of SCAF are incrementally more likely to progress to episodes of SCAF &gt;23 h as time progresses. While only around 30-40% of SCAF events are temporally related to stroke events, the presence of SCAF likely represents an important risk marker for stroke. Ongoing trials of anticoagulation in patients with SCAF durations less than 24 h will inform clinical practice and are highly anticipated. Further studies are needed to clarify the association between SCAF and clinical outcomes as well as the factors that modify this association