Presentation on theme: "Incremental Reduction in Risk of Death Associated with Use of Guideline- Recommended Therapies in Patients with Heart Failure: A Nested Case Control Analysis."— Presentation transcript:
Incremental Reduction in Risk of Death Associated with Use of Guideline- Recommended Therapies in Patients with Heart Failure: A Nested Case Control Analysis of IMPROVE HF Gregg C. Fonarow, Nancy M. Albert, Anne B. Curtis, Mihai Gheorghiade, Yang Liu, Mandeep R. Mehra, Christopher M. O'Connor, Dwight Reynolds, Mary N. Walsh, Clyde W. Yancy Fonarow GC, et al. J Am Heart Assoc. 2012;1:16-26.
Disclosures The IMPROVE HF registry is sponsored by Medtronic The sponsor had no role or input into the selection of end points or quality measures used in the study Outcome Sciences, Inc., a contract research organization, independently performed the practice site chart abstractions for IMPROVE HF, stored the data, and provided benchmarked quality of care reports to practice sites. Outcome Sciences received funding from Medtronic. Individually identifiable practice site data were not shared with either the steering committee or the sponsor Individual author disclosures are provided in the manuscript Fonarow GC, et al. J Am Heart Assoc. 2012;1:16-26.
Background: IMPROVE HF Nested Matched Case-Control Analysis Despite evidence from clinical trials, questions remain about translation of efficacy and safety of guideline-recommended heart failure (HF) therapies to real-world effectiveness in clinical practice A few observational study analyses explored the association between application of guideline-recommended therapies with clinical outcomes in HF, but not specific and incremental contributions of each therapy The goal of this analysis was to evaluate individual and incremental benefits for guideline-recommended HF therapies associated with 24-month survival Fonarow GC, et al. J Am Heart Assoc. 2012;1:16-26.
Background: IMPROVE HF Nested Matched Case-Control Analysis New HF therapies are tested on a background of existing guideline-recommended therapies, and relative clinical value of each new guideline-recommended therapy, independent of other therapies, has not been well studied Consequently with new evidence, professional society guidelines usually recommend that each new therapy be added to other established therapies Observational clinical and comparative effectiveness research has the potential to better inform clinical decision making Fonarow GC, et al. J Am Heart Assoc. 2012;1:16-26.
Study Objectives The objectives of this study were to: 1)Evaluate the individual benefits associated with each of seven current ACC/AHA guideline-recommended therapies for HF and their association with 24-month survival in outcomes with chronic HF and reduced LVEF. 2)Determine the incremental gains associated with the guideline-recommended therapies on 24-month survival. Fonarow GC, et al. J Am Heart Assoc. 2012;1:16-26.
Methods: Definition of Cases and Controls A nested matched case-control design was used because a large cohort of patients was available, enabling more explicit control of known powerful confounders, and because analysis would be less impacted by loss to follow-up. Cases: Patient with HF who died from ANY cause within 24 months of follow-up (all-cause mortality used because less subject to interpretation). Controls: Cohort patients who survived to 24 months. Fonarow GC, et al. J Am Heart Assoc. 2012;1:16-26.
Methods: Matching Cases/Controls matched on basis of their propensity score, and matched at 1:2 ratio using Greedy matching technique Logistic regression model used to generate probability of death Matches generated on the basis of non-missing covariates Per subsequent slides, cases and controls were generally well-matched Fonarow GC, et al. J Am Heart Assoc. 2012;1:16-26.
Methods: Guideline-Recommended Therapies Seven ACC/AHA HF guideline-recommended therapies (Class I) were prospectively selected: –Angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) –ß-blocker –Aldosterone antagonist –Anticoagulation therapy for atrial fibrillation/flutter (AF) –Cardiac resynchronization therapy with or without ICD (CRT) –Implantable cardioverter defibrillator with or without CRT (ICD) –Heart failure (HF) education Each therapy selected on basis of potential to improve patient outcomes, precision of definition, construct and content validity, and feasibility Patients who met guidelines-specified eligibility criteria for each individual therapy (with no contraindication, intolerance, or other documented reasons for not receiving it) were eligible for inclusion in the analyses for that therapy Fonarow GC, et al. J Am Heart Assoc. 2012;1:16-26.
Statistical Methods For each HF therapy, for eligible patients, the unadjusted odds ratio of death was determined using a logistic regression model with the therapy as the predictor variable and no covariate adjustment A univariate logistic regression analysis was then performed for each patient and practice characteristic assessed in this study to identify potential covariates for the multivariate logistic model These characteristics were fitted into a multivariate logistic regression model, with treatment as the main effect and the potential confounders as covariates, to determine the OR of death for each therapy among therapy-eligible patients who received the treatment at baseline versus therapy-eligible patients who did not receive baseline treatment in each study group Therapies were sequenced on the basis of their β-coefficients and the order in which they are commonly prescribed in clinical practice An additional set of analyses was conducted to evaluate the association between total number of guideline-recommended therapies received by all patients at baseline and death within 24 months Fonarow GC, et al. J Am Heart Assoc. 2012;1:16-26.
Results: Baseline Patient Characteristics for the 1:2 Matched Cohort Characteristics Cohort P Total (n = 4,128))Case (Dead) (n = 1,376)Control (Alive) (n = 2,752) Age, mean (SD), y71.7 (11.8)72.0 (12.4)71.6 (11.5)0.2396 Sex, n (%) Male Female 2,966 (71.9%) 1,162 (28.1%) 980 (71.2%) 396 (28.8%) 1,986 (72.2%) 766 (27.8%) 0.5246 Race, n (%) Black/African American White Other Not documented/Missing 377 (9.1%) 1,869 (45.3%) 69 (1.7%) 1,813 (43.9%) 145 (10.5%) 627 (45.6%) 14 (1.0%) 590 (42.9%) 232 (8.4%) 1,242 (45.1%) 55 (2.0%) 1,223 (44.4%) 0.0006 Insurance, n (%) Medicare Medicaid Private/Commercial Other None Not documented/Missing 2,829 (68.5%) 134 (3.2%) 786 (19.0%) 118 (2.9%) 37 (0.9%) 224 (5.4%) 953 (69.3%) 52 (3.8%) 242 (17.6%) 43 (3.1%) 12 (0.9%) 74 (5.4%) 1,876 (68.2%) 82 (3.0%) 544 (19.8%) 75 (2.7%) 25 (0.9%) 150 (5.5%) 0.4963 Ischemic HF etiology, n (%)2,893 (70.1%)996 (72.6%)1,897 (69.3%)0.0781 Previous MI1,715 (41.5%)557 (40.5%)1,158 (42.1%)0.3258 History of CABG1,413 (34.2%)476 (34.6%)937 (34.0%)0.7279 History of PCI1,082 (26.2%)361 (26.2%)721 (26.2%)0.9800 History of Atrial Fibrillation1,474 (35.7%)492 (35.8%)982 (35.7%)0.9634 Fonarow GC, et al. J Am Heart Assoc. 2012;1:16-26.
Characteristics Cohort P Total (n = 4,128)Case (Dead) (n = 1,376)Control (Alive) (n = 2,752) History of Hypertension2,612 (63.3%)874 (63.5%)1,738 (63.2%)0.8194 History of Diabetes1,464 (35.5%)495 (36%)969 (35.2%)0.6290 History of COPD801 (19.4%)285 (20.7%)516 (18.8%)0.1329 History of PVD514 (12.5%)176 (12.8%)338 (12.3%)0.6407 History of Depression410 (9.9%)151 (11.0%)259 (9.4%)0.1136 NYHA Class, n (%) I II III IV Not Documented 1,335 (32.3%) 1,612 (39.1%) 990 (24.0%) 84 (2%) 107 (2.6%) 419 (30.5%) 558 (40.6%) 331 (24.1%) 34 (2.5%) 916 (33.3%) 1,054 (38.3%) 659 (23.9%) 50 (1.8%) 73 (2.7%) 0.2379 LVEF, % Mean (SD) Median (25 th, 75 th percentiles) 25.1 (7) 25 (20, 30) 24.9 (7) 25 (20, 30) 25.2 (7) 25 (20, 30) 0.3102 Blood Pressure Systolic, mmHg, median (25 th, 75 th percentiles) Diastolic, mmHg, median (25 th, 75 th percentiles) 118 (106, 130) 70 (60, 76) 118 (106, 130) 69 (60, 76) 118 (108, 130) 70 (60, 76) 0.7506 0.0785 Results: Baseline Patient Characteristics for the 1:2 Matched Cohort Fonarow GC, et al. J Am Heart Assoc. 2012;1:16-26.
Characteristics Cohort P Total (n = 4,128)Case (Dead) (n = 1,376)Control (Alive) (n = 2,752) Resting HR, bpm, Median (25 th, 75 th percentile) 72 (64, 80) 71.5 (64, 79)0.7007 Pulmonary Rales on last exam, n (%)144 (3.5%)41 (3.0%)103 (3.7%)0.4515 Edema on last exam, n (%)896 (21.7%)313 (22.7%)583 (21.2%)0.5173 Serum Sodium, mEq/L median (25 th, 75 th percentiles) 140 (137, 142)139 (137, 142)140 (137, 142)0.5941 Serum Urea Nitrogen, mg,dL Median (25 th, 75 th percentiles) 23 (17, 31)23 (17, 32)23 (17, 30.5)0.3465 Serum Creatinine, mg/dL Median (25 th, 75 th percentiles) 1.3 (1.0, 1.6) 0.1723 Serum Potassium, mEq/L Median (25 th, 75 th percentiles) 4.4 (4.1, 4.7)4.4 (4.1, 4.8)4.4 (4.1, 4.7)0.8566 QRS Duration, ms Median (25 th, 75 th percentiles) 130 (102, 160)126 (104, 158)132 (102, 160)0.7010 Fonarow GC, et al. J Am Heart Assoc. 2012;1:16-26. Results: Baseline Patient Characteristics for the 1:2 Matched Cohort
Results: Practice Characteristics Characteristics Cohort P Total (n = 4,128)Case (Dead) (n = 1,376)Control (Alive) (n = 2,752) Census Region, n (%) South West Central Northeast 1,613 (39.1%) 584 (14.1%) 800 (19.4%) 1131 (27.4%) 553 (40.2%) 185 (13.4%) 258 (18.8%) 380 (27.6%) 1,060 (38.5%) 399 (14.5%) 542 (19.7%) 751 (27.3%) 0.6075 Outpatient Practice Setting, n (%) Non-university, non-teaching Non-university, teaching University, teaching 2,821 (68.3%) 914 (22.1%) 393 (9.5%) 943 (68.5%) 316 (23.0%) 117 (8.5%) 1,878 (68.2%) 598 (21.7%) 276 (10%) 0.2360 Multi-specialty, n (%)943 (22.8%)325 (23.6%)618 (22.5%)0.4015 Electronic health record system, n (%) Paper Electronic Mixed 1,933 (46.8%) 1,443 (35.0%) 752 (18.2%) 636 (46.2%) 473 (34.4%) 267 (19.4%) 1,297 (47.1%) 970 (35.2%) 485 (17.6%) 0.3758 HF Nurse in practice (>1FTE APN), n (%)1698 (41.1%)553 (40.2%)1145 (41.6%)0.3628 No. of electrophysiologists in practice Mean (SD) Median (25 th, 75 th percentile) 1.7 (1.7) 1 (0, 3) 1.7 (1.7) 1 (0, 3) 1.7 (1.8) 1 (0, 3) 0.4108 No. of interventionalists in practice Mean (SD) Median (25 th, 75 th percentile) 5.1 (3.3) 5 (3, 6) 5.0 (3.3) 5.0 (3, 6) 5.1 (3.3) 5.0 (3, 6) 0.6872 No. of HF clinic sessions in practice Mean (SD) Median (25 th, 75 th percentiles) 1.5 (0.5) 2 (1, 2) 1.5 (0.5) 2 (1, 2) 1.5 (0.5) 2 (1, 2) 0.9649 No. of cardiologists in practice Mean (SD) Median (25 th, 75 th percentiles) 13.9 (11.6) 10 (7, 18) 13.6 (10.9) 10 (7, 18.5) 14 (11.9) 10 (7, 18) 0.2364 No. of HF patients managed annually Mean (SD) Median (25 th, 75 th percentiles) 3,601 (3968.6) 2,319 (700, 5000) 3,565 (3820.2) 2,319 (750, 5000) 3,619.4 (4043) 2,319 (700, 5000) 0.6948 Fonarow GC, et al. J Am Heart Assoc. 2012;1:16-26.
Results: Use of Guideline-Recommended Therapies in Cases (Dead) and Controls (Alive) Use of guideline-recommended therapies at baseline in cases and controls. Baseline use of each of the therapies for cases (dead at 24 months) compared to controls (alive at 24 months). Fonarow GC, et al. J Am Heart Assoc. 2012;1:16-26.
Results: Mortality Reduction Based on Number of Guideline-Recommended Therapies at Baseline 24-Month Mortality Adjusted Odds Ratios (95% CI Displayed) Number of Therapies (vs. 0 or 1 therapy) 2 therapies 3 therapies 4 therapies 5, 6, or 7 therapies Odds Ratio (95% confidence interval) 0.63 (0.47-0.85) (p = 0.0026) 0.38 (0.29-0.51) (p < 0.0001) 0.30 (0.23-0.41) (p < 0.0001) 0.31 (0.23-0.42) (p < 0.0001) 0 0.5 1 1.5 2 Fonarow GC, et al. J Am Heart Assoc. 2012;1:16-26.
Incremental Benefits with HF Therapies (Cumulative % Reduction in Odds of Death at 24 Months) -28% to -49% P<0.0001 -54% to -71% P<0.0001 -68% to -81% P<0.0001 -75% to -86% P<0.0001 -77% to -88% P<0.0001 -72% to -87% P<0.0001 Fonarow GC, et al. J Am Heart Assoc. 2012;1:16-26.
Incremental Benefit with HF Therapi es (Cumulative % Reduction in Odds of Death at 24 Months Associated with Sequential Treatments) +20% to -68% P=0.1566 -43% to -91% P<0.0001 -70% to -96% P<0.0001 Fonarow GC, et al. J Am Heart Assoc. 2012;1:16-26.
Summary of Results Individual benefits were demonstrated for each of the guideline- recommended therapies, with a single exception The strong associations between ACEI/ARB and beta blocker use and improved survival are consistent with clinical trial data Anticoagulation for AF was associated with reduced risk of mortality CRT strongly and independently associated with improved survival ICD significantly associated with a 38% lower odds of 2-year mortality Among the individual HF therapies evaluated, beta blockers and CRT seemed to provide the greatest individual benefits In contrast, aldosterone antagonist use was NOT associated with lower mortality after multivariate adjustment, a finding which requires further study Fonarow GC, et al. J Am Heart Assoc. 2012;1:16-26.
Summary of Results The study was among the first looking at individual and incremental clinical effectiveness of guideline-recommended therapies for patients with HF and reduced LVEF Using a nested case-control design, the impact of several guideline- recommended HF therapies, applied in current clinical practice in real-world patients, could be evaluated Substantial incremental benefits demonstrated with 81-90% reduction in the odds of 24-month mortality The positive association between progressive use of therapies appeared to plateau after any 4-5 therapies were applied The ability to independently value HF therapies may provide rationale for choosing among treatments when a choice must be made – for reasons of tolerance, cost and/or adherence Fonarow GC, et al. J Am Heart Assoc. 2012;1:16-26.
Limitations: Nested Case-Control Analysis Individual therapy analyses did not adjust for use of other background therapy Even after propensity matching/risk adjustment, differential indications for each therapy as a function of HF severity may still have influenced incremental benefit analyses Other measured/unmeasured confounding variables that would have strengthened or weakened association for some or all therapies Majority of patients receiving CRT received a CRT-D device – likely diminished ability to ascertain incremental benefit of CRT in some of the analyses Associations between use of guideline-recommended therapies and mortality do not determine causality – associations may reflect clinical effectiveness, and they may alternatively reflect treatment selection bias also Fonarow GC, et al. J Am Heart Assoc. 2012;1:16-26.
Conclusions This analysis demonstrated that –Guideline-recommended therapies for patients with HF and reduced LVEF are associated with individual and incremental decreased risk of 24-month mortality Beta blocker and CRT had the strongest survival benefits observed Incremental benefit with each successive guideline-recommended therapy, plateauing after any 4-5 therapies were applied Provides further evidence for clinical effectiveness of guideline- recommended HF therapies for patients in real-world clinical practice Results suggest that benefit accrues incrementally with application of these therapies in the outpatient setting with 81-90% reductions in the odds of 24-month mortality These results provide further rationale for using systems, performance improvement, and HF disease management to ensure the implementation of guideline-recommended HF therapies into clinical practice Fonarow GC, et al. J Am Heart Assoc. 2012;1:16-26.
IMPROVE HF Study Overview Largest, most comprehensive performance improvement study for HF patients in the outpatient setting Designed to enhance quality of care of HF patients by facilitating adoption of evidence-based, guideline-recommended therapies: –Evaluate utilization rates of evidence-based, guideline-recommended HF therapies at baseline and over the course of the performance improvement intervention (chart audit and feedback; use of performance measures) –Multifaceted, practice-specific performance improvement toolkit including clinical decision support tools (reminder systems) –Sites attended an educational workshop to set treatment goals and develop a customized clinical care pathway (educational outreach) Fonarow GC, et al. Am Heart J. 2007;154:12-38.
Patient Population To be enrolled in IMPROVE HF, patients had to have heart failure or post-myocardial infarction left ventricular dysfunction with left ventricular ejection fraction of 35% or less There were 15,177 patients from 167 cardiology and multispecialty practices in the United States evaluated at baseline and enrolled in the longitudinal cohort At the 24-month follow-up 11,621 of the 15,177 patients (76.6%) had documentation of vital status A total of 2,507 patients (16.5%) were lost to follow-up and 1,048 (6.9%) were seen in practices (n = 12) that did not complete the follow-up assessment Fonarow GC, et al. Circulation. 2011;123:1601-1610.
Methods: Study Design and Patient Disposition Longitudinal Cohort Two Single- Time-Point Cohorts Process Improvement Intervention (165 sites) Baseline Chart Review 167 sites 15,177 patients 12-Month Chart Review 155 sites 9,386 patients 24-Month Chart Review 155 sites 7,605 patients 6-Month Chart Review 154 sites 9,992 patients Total Sites167 Patients Enrolled34,810 Total Chart Reviews63,143 Total # of Site Visits782 18-Month Chart Review 151 sites 9,641 patients Longitudinal cohort included the same patients reviewed at 3 time points Single-time-point cohorts included separate patients from the same practices and unique from the longitudinal cohort, as well as from each other Fonarow GC, et al. Circulation. 2010;122:585-596.
Methods: Guideline-Recommended Quality Measures Seven quality measures with strong evidence prospectively selected: –Angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB)* –ß-blocker* –Aldosterone antagonist –Anticoagulation therapy for atrial fibrillation/flutter (AF)* –Cardiac resynchronization therapy with or without ICD (CRT) –Implantable cardioverter defibrillator with or without CRT (ICD) –Heart failure (HF) education* Patients deemed eligible for individual quality measure based on meeting guideline criteria, without contraindications, intolerance, or other documented reasons for non-treatment Steering committee selected quality measures based on potential to improve patient outcomes, definition precision, construct and content validity, feasibility * Included as ACC/AHA outpatient HF performance measure, endorsed by National Quality Forum. Fonarow GC, et al. Circulation. 2010;122:585-596.
IMPROVE HF Outpatient Process Measures Yancy CW, et al. Circulation. 2005;112:154-e235. Bonow RO, et al. J Am Coll Cardiol. 2005;46:1144-1178.
Methods: Patient Selection, Practice Selection, Data Collection, and Management Patient Inclusion: –Clinical diagnosis of HF or prior MI with at least two prior clinic visits within 2 years –LVEF ≤ 35% or moderate to severe left ventricular dysfunction Patient Exclusion: –Cardiac transplantation –Estimated survival < 1 year from non-cardiovascular condition Average of 90 eligible patients per practice randomly selected for each of three study cohorts Practices: Outpatient cardiology (single specialty or multi-specialty) practices from all regions of the country Data quality measures –34 trained, tested chart review specialists –Training oversight by study steering committee members –Monthly quality reports –Automated data field range, format, unit checks Chart abstraction quality –Interrater reliability averaged 0.82 (kappa statistic) –Source documentation audit sample concordance rate range of 92.3% to 96.3% Coordinating center: Outcome Sciences, Inc. (Cambridge, MA) –Individual practice data not shared with sponsor or steering committee Fonarow GC, et al. Circulation. 2010;122:585-596.
Methods: Study Design and Patient Disposition Patients who were eligible for treatment but not treated at baseline and who crossed over within the first 12 months of the intervention were excluded from each measure Fonarow GC, et al. Circulation. 2010;122:585-596.
Methods: Practice Specific Performance Improvement Intervention Practice Survey: 96% adopted one or more performance improvement strategies 85% used benchmarked quality reports 60% employed one or more IMPROVE HF tools * Use or participation was encouraged but not mandatory. Practices could adopt or modify tools. Fonarow GC, et al. Circulation. 2010;122:585-596. -
IMPROVE HF Performance Intervention: Benchmarked Practice Profile Report
IMPROVE HF Performance Improvement Tools As part of an enhanced treatment plan, IMPROVE HF provided evidence-based best-practices algorithms, clinical pathways, standardized encounter forms, checklists, pocket cards, chart stickers, and patient education and other materials to facilitate improved management of outpatients with HF The materials can be downloaded from www.improvehf.com The materials are also included in the Circulation online-only Data Supplement Fonarow GC, et al. Circulation. 2010;122:585-596.
IMPROVE HF Practice Specific Education and Implementation Tools www.improvehf.com Evidence Based Algorithms and Pocket Cards Patient Education Materials Clinical Assessment and Management Forms Clinical Trials and Current Guidelines Dissemination of best practices: Webcasts Online Education Newsletters
Brief Statement Indications Implantable cardioverter defibrillators (ICDs) are indicated for ventricular antitachycardia pacing and ventricular defibrillation for automated treatment of life-threatening ventricular arrhythmias. Cardiac Resynchronization Therapy (CRT) ICDs are indicated for ventricular antitachycardia pacing and ventricular defibrillation for automated treatment of life-threatening ventricular arrhythmias and for the reduction of the symptoms of moderate to severe heart failure (NYHA Functional Class III or IV) in those patients who remain symptomatic despite stable, optimal medical therapy and have a left ventricular ejection fraction less than or equal to 35% and a prolonged QRS duration. CRT IPGs are indicated for the reduction of the symptoms of moderate to severe heart failure (NYHA Functional Class III or IV) in those patients who remain symptomatic despite stable, optimal medical therapy, and have a left ventricular ejection fraction less than or equal to 35% and a prolonged QRS duration. Contraindications IPGs and CRT IPGs are contraindicated for dual chamber atrial pacing in patients with chronic refractory atrial tachyarrhythmias; asynchronous pacing in the presence (or likelihood) of competitive paced and intrinsic rhythms; unipolar pacing for patients with an implanted cardioverter defibrillator because it may cause unwanted delivery or inhibition of ICD therapy; and certain IPGs are contraindicated for use with epicardial leads and with abdominal implantation. ICDs and CRT ICDs are contraindicated in patients whose ventricular tachyarrhythmias may have transient or reversible causes, patients with incessant VT or VF, and for patients who have a unipolar pacemaker. Warnings/Precautions Changes in a patient’s disease and/or medications may alter the efficacy of the device’s programmed parameters. Patients should avoid sources of magnetic and electromagnetic radiation to avoid possible underdetection, inappropriate sensing and/or therapy delivery, tissue damage, induction of an arrhythmia, device electrical reset, or device damage. Do not place transthoracic defibrillation paddles directly over the device. Additionally, for CRT ICDs and CRT IPGs, certain programming and device operations may not provide cardiac resynchronization. Also for CRT IPGs, Elective Replacement Indicator (ERI) results in the device switching to VVI pacing at 65 ppm. In this mode, patients may experience loss of cardiac resynchronization therapy and/or loss of AV synchrony. For this reason, the device should be replaced prior to ERI being set. Potential Complications Potential complications include, but are not limited to, rejection phenomena, erosion through the skin, muscle or nerve stimulation, oversensing, failure to detect and/or terminate arrhythmia episodes, and surgical complications such as hematoma, infection, inflammation, and thrombosis. An additional complication for ICDs and CRT ICDs is the acceleration of ventricular tachycardia. See the device manual for detailed information regarding the implant procedure, indications, contraindications, warnings, precautions, and potential complications/adverse events. For further information, please call Medtronic at 1 (800) 328-2518 and/or consult Medtronic’s website at www.medtronic.com. Caution: Federal law (USA) restricts these devices to sale by or on the order of a physician. UC201205289 EN February 2012
Your consent to our cookies if you continue to use this website.