Matthias Trampisch

Risk factors for acute kidney injury following TA-TAVI or minimally invasive aortic valve replacement: which procedure is less kidney damaging in elderly patients?

BACKGROUND Acute kidney injury (AKI) represents a major complication following aortic valve replacement in elderly patients. The aim of this study was to determine possible risk factors for AKI and to find the ideal strategy, minimally invasive valve replacement (MIS-AVR) or transapical valve implantation (TA-TAVI), regarding the postoperative renal outcome. METHODS A total of 133 patients (age ≥ 75 years, 67 male) with severe aortic stenosis were included over 2 years: 42% were treated with MIS-AVR, 58% underwent TA-TAVI procedure. AKI was considered as a postprocedural 1.5× increase in creatinine or an increase of > 0.3 mg/dL/48 hours. Group differences were tested with chi-square or t-test. AKI risk assumption was analyzed in multiple multivariate logistic regression models. RESULTS EuroSCORE II-related risk assumption was 8.7 ± 6.9 for TA-TAVI and 4.5 ± 5.7 for MIS-AVR (p < 0.001). The overall 30-day survival rate was 93%. Fifty-eight patients developed a risk for AKI and 13 developed a manifest renal injury/failure. Logistic regression analysis revealed a higher AKI risk for TA-TAVI (odds ratio, OR = 2.58; 95% confidence interval, CI = 1.18, 5.63; p = 0.017). EuroSCORE II (OR = 0.98; 95% CI = 0.92, 1.04; p = 0.433); preoperative creatinine (OR = 1.78; 95% CI = 0.67, 4.77; p = 0.249) and estimated glomerular filtration rate (OR = 1.00; 95% CI = 0.97, 1.02; p = 0.655) had no impact on AKI. A regression model adjusting for the variables age, gender, body mass index (BMI), diabetes, and procedure type revealed a higher AKI rate for male gender (OR = 2.41; 95% CI = 1.13, 5.11; p =  0.022). Operation time and radio-contrast media volume had no influence on the AKI-occurrence. There was no correlation between AKI and early mortality. CONCLUSION A higher risk for AKI after TA-TAVI should be considered in the therapy decision, especially in elderly male patients because MIS-AVR still yields excellent results.

Recruiting Hard-to-Reach Subjects for Exercise Interventions: A Multi-Centre and Multi-Stage Approach Targeting General Practitioners and Their Community-Dwelling and Mobility-Limited Patients

The general practitioner (GP)’s practice appears to be an ideal venue for recruiting community-dwelling older adults with limited mobility. This study (Current Controlled Trials ISRCTN17727272) aimed at evaluating the recruiting process used for a multi-centre exercise intervention (HOMEfit). Each of six steps resulted in an absolute number of patients (N1–N6). Sex and age (for N4–N6) and reasons for dropping out were assessed. Patient database screening (N1–N3) at 15 GP practices yielded N1 = 5,990 patients aged 70 and above who had visited their GP within the past 6 months, N2 = 5,467 after exclusion of institutionalised patients, N3 = 1,545 patients eligible. Using a pre-defined limitation algorithm in order to conserve the practices’ resources resulted in N4 = 1,214 patients (80.3 ± 5.6 years, 68% female), who were then officially invited to the final assessment of eligibility at the GP’s practice. N5 = 434 patients (79.5 ± 5.4 years, 69% female) attended the practice screening (n = 13 of whom had not received an official invitation). Finally, N6 = 209 (79.8 ± 5.2 years, 74% female) were randomised after they were judged eligible and had given their written informed consent to participate in the randomised controlled trial (overall recruitment rate: 4.4%). The general strategy of utilising a GP’s practice to recruit the target group proved beneficial. The data and experiences presented here can help planners of future exercise-intervention studies.

The risk of peripheral artery disease in older adults - seven-year results of the getABI study

BACKGROUND To assess the risk of peripheral artery disease (PAD) in older adults and the contribution of traditional and novel risk factors to the incidence of PAD. PATIENTS AND METHODS 344 general practitioners (GPs), trained by vascular specialists all over Germany, enrolled 6,880 unselected participants aged 65 years or older (getABI study). The onset of PAD was determined by a regression method in the course of repeated measurements of the ankle brachial index (ABI) over seven years. PAD onset was defined by the declining linear regression ABI line reaching 0.9 or by PAD symptoms. RESULTS The cumulative PAD incidence over seven years was 12.9%, corresponding to an incidence rate of 20.3 per 1000 person years (95% confidence interval [95%CI] 18.8 to 21.7). Logistic regression analysis showed that traditional risk factors contributed significantly to the risk of PAD: current smoker status (odds ratio 2.65, 95%CI 2.08 to 3.37), diabetes (1.35, 95%CI 1.13 to 1.62), and low-density lipoprotein >130 mg/dl (1.26, 95%CI 1.07 to 1.48). Three novel risk factor candidates showed significant impact on PAD incidence: elevated sensitive C-reactive protein level (1.23, 95%CI 1.05 to 1.45), impaired estimated glomerular filtration rate (1.27, 95%CI 1.03 to 1.56), and elevated homocysteine level (1.19, 95%CI 1.01 to 1.41). CONCLUSIONS Older adults in Germany have a PAD risk of 12.9% per seven years. Potentially modifiable traditional PAD risk factors yield high impact on PAD incidence. Novel risk factor candidates may contribute to the risk of PAD.

Assessing the similarity of dose response and target doses in two non-overlapping subgroups

We consider 2 problems of increasing importance in clinical dose finding studies. First, we assess the similarity of 2 non-linear regression models for 2 non-overlapping subgroups of patients over a restricted covariate space. To this end, we derive a confidence interval for the maximum difference between the 2 given models. If this confidence interval excludes the pre-specified equivalence margin, similarity of dose response can be claimed. Second, we address the problem of demonstrating the similarity of 2 target doses for 2 non-overlapping subgroups, using again an approach based on a confidence interval. We illustrate the proposed methods with a real case study and investigate their operating characteristics (coverage probabilities, Type I error rates, power) via simulation.

Optimal Designs for Quantile Regression Models

Despite their importance, optimal designs for quantile regression models have not been developed so far. In this article, we investigate the D-optimal design problem for nonlinear quantile regression analysis. We provide a necessary condition to check the optimality of a given design and use it to determine bounds for the number of support points of locally D-optimal designs. The results are illustrated, determining locally, Bayesian and standardized maximin D-optimal designs for quantile regression analysis in the Michaelis–Menten and EMAX model, which are widely used in such important fields as toxicology, pharmacokinetics, and dose–response modeling.

Long-term safety of tiotropium/olodaterol Respimat ® in patients with moderate-to-very severe COPD and renal impairment in the TONADO ® studies

Introduction The safety, lung function efficacy, and symptomatic benefits of combined tiotropium and olodaterol in patients with COPD were established in the 1-year TONADO® studies (NCT01431274; NCT01431287). As tiotropium is predominantly excreted by the kidneys, the long-term safety profile of tiotropium/olodaterol was investigated in patients with renal impairment in a prespecified safety analysis of the TONADO studies. Methods These were 2 replicate, randomized, double-blind, parallel-group, 52-week Phase III studies that assessed tiotropium/olodaterol compared with tiotropium or olodaterol alone (all via Respimat®) in patients with moderate-to-very severe COPD. In this analysis, renal impairment was defined as mild (creatinine clearance [CLcr] 60–89 mL/min), moderate (CLcr 30–59 mL/min) or severe (CLcr 15–29 mL/min). Adverse events (AEs) were pooled from both studies. Results Of 3,041 patients included in this analysis, 1,333 (43.8%) had mild, 404 (13.3%) had moderate, and 5 (0.2%) had severe renal impairment; these were distributed equally between treatment groups. Almost one-quarter of all treated patients (23.4%) had a history of cardiac disorder, 45.6% had hypertension, and 13.3% had glucose metabolism disorders, including diabetes. AEs with olodaterol, tiotropium, and tiotropium/olodaterol occurred in 75.1%, 70.8%, and 72.0% of patients with no renal impairment, 75.7%, 74.0%, and 73.3% with mild renal impairment, and 84.3%, 79.5%, and 79.7% with moderate renal impairment, respectively. There was no notable effect of renal impairment on the proportion of patients with an AE, and no differences were observed between tiotropium/olodaterol versus the monocomponents. There was no difference in the incidence of major adverse cardiac events, renal and urinary tract AEs, or potential anticholinergic effects with increasing severity of renal impairment. Conclusion Over half the patients enrolled in the TONADO studies had renal impairment, and there was a high level of pre-existing cardiovascular comorbidity. The safety and tolerability of tiotropium/olodaterol is comparable to the monocomponents, irrespective of the level of renal impairment.

Pharmacokinetic Interaction between Faldaprevir and Cyclosporine or Tacrolimus in Healthy Volunteers: A Prospective, Open‐Label, Fixed‐Sequence, Crossover Study

Faldaprevir (FDV) is a potent, orally administered inhibitor of hepatitis C virus. In this single‐centre, open‐label, fixed‐sequence, crossover study of 32 healthy adult male and female volunteers, subjects received either a single dose of cyclosporine (CsA) 50 mg (N = 16) or tacrolimus (TAC) 0.5 mg (N = 16), followed by a washout of at least 14 days. Each subject then received a loading dose of FDV 240 mg followed by 120 mg FDV once daily for 6 days. FDV 120 mg was then co‐administered with an additional single dose of CsA (50 mg) or TAC (0.5 mg), followed by an additional 6 days of FDV 120 mg once daily. Intensive blood sampling was performed to assess the PK interaction potential. Assessment of relative BA indicated that exposure to CsA co‐administered with FDV was similar to CsA alone. However, the AUCτ,ss and Cmax,ss of FDV were increased by 23% and 41%, respectively, when FDV was co‐administered with CsA. Exposure to TAC was slightly increased (AUC0‐∞ increased by 27%, no change in Cmax) when TAC was co‐administered with FDV. In contrast, exposure to FDV co‐administered with TAC was similar to FDV alone. No unexpected safety findings arose from the trial. The limitations of the study (use of single, low dose of TAC and CsA, and only healthy volunteers in the trial) are discussed.