Rodney A. Hayward

Glucose Control and Vascular Complications in Veterans with Type 2 Diabetes

BACKGROUND The effects of intensive glucose control on cardiovascular events in patients with long-standing type 2 diabetes mellitus remain uncertain. METHODS We randomly assigned 1791 military veterans (mean age, 60.4 years) who had a suboptimal response to therapy for type 2 diabetes to receive either intensive or standard glucose control. Other cardiovascular risk factors were treated uniformly. The mean number of years since the diagnosis of diabetes was 11.5, and 40% of the patients had already had a cardiovascular event. The goal in the intensive-therapy group was an absolute reduction of 1.5 percentage points in the glycated hemoglobin level, as compared with the standard-therapy group. The primary outcome was the time from randomization to the first occurrence of a major cardiovascular event, a composite of myocardial infarction, stroke, death from cardiovascular causes, congestive heart failure, surgery for vascular disease, inoperable coronary disease, and amputation for ischemic gangrene. RESULTS The median follow-up was 5.6 years. Median glycated hemoglobin levels were 8.4% in the standard-therapy group and 6.9% in the intensive-therapy group. The primary outcome occurred in 264 patients in the standard-therapy group and 235 patients in the intensive-therapy group (hazard ratio in the intensive-therapy group, 0.88; 95% confidence interval [CI], 0.74 to 1.05; P=0.14). There was no significant difference between the two groups in any component of the primary outcome or in the rate of death from any cause (hazard ratio, 1.07; 95% CI, 0.81 to 1.42; P=0.62). No differences between the two groups were observed for microvascular complications. The rates of adverse events, predominantly hypoglycemia, were 17.6% in the standard-therapy group and 24.1% in the intensive-therapy group. CONCLUSIONS Intensive glucose control in patients with poorly controlled type 2 diabetes had no significant effect on the rates of major cardiovascular events, death, or microvascular complications with the exception of progression of albuminuria (P = 0.01) [added]. (ClinicalTrials.gov number, NCT00032487.)

Reliability and validity testing of the Michigan Hand Outcomes Questionnaire

In this study, psychometric principles were used to develop an outcomes questionnaire capable of measuring health state domains important to patients with hand disorders. These domains were hypothesized to include (1) overall hand function, (2) activities of daily living (ADL), (3) pain, (4) work performance, (5) aesthetics, and (6) patient satisfaction with hand function. An initial pool of 100 questions was pilot-tested for clarity in 20 patients; following factor analysis, the number of questions was reduced to a 37-item Michigan Hand Outcomes Questionnaire (MHQ). The MHQ, along with the Short Form-12, a generic health status outcomes questionnaire, was then administered to 200 consecutive patients at a university-based hand surgery clinic and was subjected to reliability and validity testing. The mean time required to complete the questionnaire was 10 minutes (range, 7-20 minutes). Factor analysis supported the 6 hypothesized scales. Test-retest reliability using Spearmans correlation demonstrated substantial agreement, ranging from 0.81 for the aesthetics scale to 0.97 for the ADL scale. In testing for internal consistency, Cronbachs alphas ranged from 0.86 for the pain scale to 0.97 for the ADL scale (values >0.7 for Cronbachs alpha are considered a good internal consistency). Correlation between scales gave evidence of construct validity. In comparing similar scales in the MHQ and the Short Form-12, a moderate correlation (range, 0.54-0.79) for the ADL, work performance, and pain scales was found. In evaluating the discriminate validity of the aesthetics scale, a significant difference (p = .0012) was found between the aesthetics scores for patients with carpal tunnel syndrome and patients with rheumatoid arthritis. The MHQ is a reliable and valid instrument for measuring hand outcomes. It can be used in a clinic setting with minimal burden to patients. The questions in the MHQ have undergone rigorous psychometric testing, and the MHQ is a promising instrument for evaluation of outcomes following hand surgery.

The relative importance of physician communication, participatory decision making, and patient understanding in diabetes self-management

AbstractOBJECTIVE: Patients’ self-management practices have substantial consequences on morbidity and mortality in diabetes. While the quality of patient-physician relations has been associated with improved health outcomes and functional status, little is known about the impact of different patient-physician interaction styles on patients’ diabetes self-management. This study assessed the influence of patients’ evaluation of their physicians’ participatory decision-making style, rating of physician communication, and reported understanding of diabetes self-care on their self-reported diabetes management. DESIGN: We surveyed 2,000 patients receiving diabetes care across 25 Veterans’ Affairs facilities. We measured patients’ evaluation of provider participatory decision making with a 4-item scale (Provider Participatory Decision-making Style [PDMstyle]; α=0.96), rating of providers’ communication with a 5-item scale (Provider Communication [PCOM]; α=0.93), understanding of diabetes self-care with an 8-item scale (α=0.90), and patients’ completion of diabetes self-care activities (self-management) in 5 domains (α=0.68). Using multivariable linear regression, we examined self-management with the independent associations of PDMstyle, PCOM, and Understanding. RESULTS: Sixty-six percent of the sample completed the surveys (N=1,314). Higher ratings in PDMstyle and PCOM were each associated with higher self-management assessments (P<.01 in all models). When modeled together, PCOM remained a significant independent predictor of self-management (standardized β: 0.18; P<.001), but PDMstyle became nonsignificant. Adding Understanding to the model diminished the unique effect of PCOM in predicting self-management (standardized β: 0.10; P=.004). Understanding was strongly and independently associated with self-management (standardized β: 0.25; P<.001). CONCLUSION: For these patients, ratings of providers’ communication effectiveness were more important than a participatory decision-making style in predicting diabetes self-management. Reported understanding of self-care behaviors was highly predictive of and attenuated the effect of both PDMstyle and PCOM on self-management, raising the possibility that both provider styles enhance self-management through increased patient understanding or self-confidence.

Comparison of Quality of Care for Patients in the Veterans Health Administration and Patients in a National Sample

As methods for measuring the quality of medical care have matured, widespread quality problems have become increasingly evident (1, 2). The solution to these problems is much less obvious, however, particularly with regard to large delivery systems. Many observers have suggested that improved information systems, systematic performance monitoring, and coordination of care are necessary to enhance the quality of medical care (3). Although the use of integrated information systems (including electronic medical records) and performance indicators has become more common throughout the U.S. health care system, most providers are not part of a larger integrated delivery system and continue to rely on traditional information systems (4). An exception is the Veterans Health Administration (VHA). As the largest delivery system in the United States, the VHA has been recognized as a leader in developing a more coordinated system of care. Beginning in the early 1990s, VHA leadership instituted both a sophisticated electronic medical record system and a quality measurement approach that holds regional managers accountable for several processes in preventive care and in the management of common chronic conditions (5, 6). Other changes include a system-wide commitment to quality improvement principles and a partnership between researchers and managers for quality improvement (7). As Jha and colleagues (8) have shown, since these changes have been implemented, VHA performance has outpaced that of Medicare in the specific areas targeted. Nevertheless, whether this improvement has extended beyond the relatively narrow scope of the performance measures is unknown. Beyond that study, the data comparing VHA care with other systems of care are sparse and mixed. For example, patients hospitalized at VHA hospitals were more likely than Medicare patients to receive angiotensin-converting enzyme inhibitors and thrombolysis after myocardial infarction (9). On the other hand, VHA patients were less likely to receive angiography when indicated and had higher mortality rates after coronary artery bypass grafting than patients in community hospitals (10, 11). Kerr and colleagues found that care for diabetes was better in almost every dimension in the VHA system than in commercial managed care (12). More extensive comparisons, especially of outpatient care, are lacking. To address these issues, a more comprehensive assessment of quality is needed. Using a broad measure of quality of care that is based on medical record review and was developed outside the VHA, we compared the quality of outpatient and inpatient care among 2 samples: 1) a national sample of patients drawn from 12 communities and 2) VHA patients from 26 facilities in 12 health care systems located in the southwestern and midwestern United States (13). We analyzed performance in the years after the institution of routine performance measurement and the electronic medical record. Using the extensive set of quality indicators included in the measurement system, we compared the overall quality of care delivered in the VHA system and in the United States, as well as the quality of acute, chronic, and preventive care across 26 conditions. In addition, we evaluated whether VHA performance was better in the specific areas targeted by the VHA quality management system. Methods Development of Quality Indicators For this study, we used quality indicators from RANDs Quality Assessment Tools system, which is described in more detail elsewhere (14-17). The indicators included in the Quality Assessment Tools system are process quality measures, are more readily actionable than outcomes measures, require less risk adjustment, and follow the structure of national guidelines (18, 19). After reviewing established national guidelines and the medical literature, we chose a subset of quality indicators from the Quality Assessment Tools system that represented the spectrum of outpatient and inpatient care (that is, screening, diagnosis, treatment, and follow-up) for acute and chronic conditions and preventive care processes representing the leading causes of morbidity, death, and health care use among older male patients. The Appendix Table lists the full indicator set, which was determined by four 9-member, multispecialty expert panels. These panels assessed the validity of the proposed indicators using the RAND/University of California, Los Angelesmodified Delphi method. The experts rated the indicators on a 9-point scale (1 = not valid; 9 = very valid), and we accepted indicators that had a median validity score of 7 or higher. This method of selecting indicators is reliable and has been shown to have content, construct, and predictive validity (20-23). Of the 439 indicators in the Quality Assessment Tools system, we included 348 indicators across 26 conditions in our study and excluded 91 indicators that were unrelated to the target population (for example, those related to prenatal care and cesarean sections). Of the 348 indicators, 21 were indicators of overuse (for example, patients with moderate to severe asthma should not receive -blocker medications) and 327 were indicators of underuse (for example, patients who have been hospitalized for heart failure should have follow-up contact within 4 weeks of discharge). Appendix Table. Comparison of Performance of the Veterans Health Administration Sample and the National Sample by Indicator Two physicians independently classified each indicator according to the type of care delivered; the function of the indicated care (screening, diagnosis, treatment, and follow-up); and whether the indicator was supported by a randomized, controlled trial, another type of controlled trial, or other evidence. Type of care was classified as acute (for example, in patients presenting with dysuria, presence or absence of fever and flank pain should be elicited), chronic (for example, patients with type 2 diabetes mellitus in whom dietary therapy has failed should receive oral hypoglycemic therapy), or preventive (for example, all patients should be screened for problem drinking). In addition, we further classified the indicators into 3 mutually exclusive categories according to whether they corresponded to the VHA performance indicators that were in use in fiscal year 1999. Twenty-six indicators closely matched the VHA indicators, 152 involved conditions that were targeted by the VHA indicators but were not among the 26 matches, and 170 did not match the VHA measures or conditions. We performed a similar process to produce a list of 15 indicators that matched contemporaneous Health Plan Employer Data and Information Set (HEDIS) performance measures (24). Table 1 shows the conditions targeted by the indicators, and Table 2 gives an example indicator for each of the conditions or types of care for which condition- or type-specific comparisons were possible. Table 1. Conditions and Number of Indicators Used in Comparisons Table 2. Example Indicators of Quality of Care Identifying Participants Patients were drawn from 2 ongoing quality-of-care studies: a study of VHA patients and a random sample of adults from 12 communities (13). The VHA patients were drawn from 26 clinical sites in 12 health care systems located in 2 Veterans Integrated Service Networks in the midwestern and southwestern United States. These networks closely match the overall Veterans Affairs system with regard to medical record review and survey-based quality measures (25, 26). We selected patients who had had at least 2 outpatient visits in each of the 2 years between 1 October 1997 and 30 September 1999. A total of 106576 patients met these criteria. We randomly sampled 689, oversampling for chronic obstructive pulmonary disease (COPD), hypertension, and diabetes, and were able to locate records for 664 patients (a record location rate of 96%). Because of resource constraints, we reviewed a random subset of 621 of these records. Since this sample contained only 20 women and 4 patients younger than 35 years of age, we further restricted the sample to men older than 35 years of age. Thus, we included 596 VHA patients in the analysis. All of these patients had complete medical records. The methods we used to obtain the national sample have been described elsewhere (13) and are summarized here. As part of a nationwide study, residents of 12 large metropolitan areas (Boston, Massachusetts; Cleveland, Ohio; Greenville, South Carolina; Indianapolis, Indiana; Lansing, Michigan; Little Rock, Arkansas; Miami, Florida; Newark, New Jersey; Orange County, California; Phoenix, Arizona; Seattle, Washington; and Syracuse, New York) were contacted by using random-digit dialing and were asked to complete a telephone survey (27). To ensure comparability with the VHA sample, we included only men older than 35 years of age. Between October 1998 and August 2000, we telephoned 4086 of these participants and asked for permission to obtain copies of their medical records from all providers (both individual and institutional) that they had visited within the past 2 years. We received verbal consent from 3138 participants (77% of those contacted by telephone). We mailed consent forms and received written permission from 2351 participants (75% of those who had given verbal permission). We received at least 1 medical record for 2075 participants (88% of those who had returned consent forms). We excluded participants who had not had at least 2 medical visits in the past 2 years to further ensure comparability with the VHA sample. Thus, our final national sample included 992 persons. The rolling abstraction period (October 1996 to August 2000) substantially overlapped the VHA sampling period. The average overlap was 70%, and all records had at least 1 year of overlap. Seven hundred eight (71%) of the 992 persons in the national sample had complete medical records. On the basis of data from the original telephone survey, we det

A Randomized Trial of Rectal Indomethacin to Prevent Post-ERCP Pancreatitis

BACKGROUND Preliminary research suggests that rectally administered nonsteroidal antiinflammatory drugs may reduce the incidence of pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP). METHODS In this multicenter, randomized, placebo-controlled, double-blind clinical trial, we assigned patients at elevated risk for post-ERCP pancreatitis to receive a single dose of rectal indomethacin or placebo immediately after ERCP. Patients were determined to be at high risk on the basis of validated patient- and procedure-related risk factors. The primary outcome was post-ERCP pancreatitis, which was defined as new upper abdominal pain, an elevation in pancreatic enzymes to at least three times the upper limit of the normal range 24 hours after the procedure, and hospitalization for at least 2 nights. RESULTS A total of 602 patients were enrolled and completed follow-up. The majority of patients (82%) had a clinical suspicion of sphincter of Oddi dysfunction. Post-ERCP pancreatitis developed in 27 of 295 patients (9.2%) in the indomethacin group and in 52 of 307 patients (16.9%) in the placebo group (P=0.005). Moderate-to-severe pancreatitis developed in 13 patients (4.4%) in the indomethacin group and in 27 patients (8.8%) in the placebo group (P=0.03). CONCLUSIONS Among patients at high risk for post-ERCP pancreatitis, rectal indomethacin significantly reduced the incidence of the condition. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00820612.).

Follow-up of Glycemic Control and Cardiovascular Outcomes in Type 2 Diabetes

BACKGROUND The Veterans Affairs Diabetes Trial previously showed that intensive glucose lowering, as compared with standard therapy, did not significantly reduce the rate of major cardiovascular events among 1791 military veterans (median follow-up, 5.6 years). We report the extended follow-up of the study participants. METHODS After the conclusion of the clinical trial, we followed participants, using central databases to identify procedures, hospitalizations, and deaths (complete cohort, with follow-up data for 92.4% of participants). Most participants agreed to additional data collection by means of annual surveys and periodic chart reviews (survey cohort, with 77.7% follow-up). The primary outcome was the time to the first major cardiovascular event (heart attack, stroke, new or worsening congestive heart failure, amputation for ischemic gangrene, or cardiovascular-related death). Secondary outcomes were cardiovascular mortality and all-cause mortality. RESULTS The difference in glycated hemoglobin levels between the intensive-therapy group and the standard-therapy group averaged 1.5 percentage points during the trial (median level, 6.9% vs. 8.4%) and declined to 0.2 to 0.3 percentage points by 3 years after the trial ended. Over a median follow-up of 9.8 years, the intensive-therapy group had a significantly lower risk of the primary outcome than did the standard-therapy group (hazard ratio, 0.83; 95% confidence interval [CI], 0.70 to 0.99; P=0.04), with an absolute reduction in risk of 8.6 major cardiovascular events per 1000 person-years, but did not have reduced cardiovascular mortality (hazard ratio, 0.88; 95% CI, 0.64 to 1.20; P=0.42). No reduction in total mortality was evident (hazard ratio in the intensive-therapy group, 1.05; 95% CI, 0.89 to 1.25; P=0.54; median follow-up, 11.8 years). CONCLUSIONS After nearly 10 years of follow-up, patients with type 2 diabetes who had been randomly assigned to intensive glucose control for 5.6 years had 8.6 fewer major cardiovascular events per 1000 person-years than those assigned to standard therapy, but no improvement was seen in the rate of overall survival. (Funded by the VA Cooperative Studies Program and others; VADT ClinicalTrials.gov number, NCT00032487.).

Treatment of Hypertension in Type 2 Diabetes Mellitus: Blood Pressure Goals, Choice of Agents, and Setting Priorities in Diabetes Care

Type 2 diabetes mellitus is a common disease with substantial associated morbidity and mortality (1, 2). Most adverse diabetes outcomes are a result of vascular complications, both at a macrovascular level (coronary artery disease, cerebrovascular disease, or peripheral vascular disease) and a microvascular level (retinopathy, nephropathy, or neuropathy) (3). Macrovascular complications are more common; up to 80% of patients with type 2 diabetes will develop or die of macrovascular disease (4-12), and the costs associated with macrovascular disease are an order of magnitude greater than those associated with microvascular disease (13). Because diabetes is defined by blood glucose levels, much of the attention in diabetes care focuses on the management of hyperglycemia. This has been magnified by the causal link between hyperglycemia and microvascular outcomes (3, 14). However, while some observational evidence suggests that level of glycemia is a risk factor for macrovascular disease (15-18), experimental studies to date have not clearly shown a causal relationship between improved glycemic control and reductions in serious cardiovascular outcomes (3, 14). Given these results and the epidemiologic characteristics of diabetes complications, it would seem more logical to focus diabetes care on prevention of macrovascular complications rather than on glucose control and microvascular complications. Indeed, the importance of preventing the macrovascular complications of type 2 diabetes has started to receive greater attention. In particular, several trials have examined the benefit of management of highly prevalent risk factors, such as hypertension. Hypertension is extremely common in patients with type 2 diabetes, affecting up to 60% (2), and there are a growing number of pharmacologic treatment options. The goals of this paper are to review the literature to evaluate effects of management of hypertension on the complications of type 2 diabetes and, based on this literature, to determine optimal blood pressure goals and choice of agents. This will provide an evidence base to guide clinicians in setting hypertension treatment goals and priorities in patients with type 2 diabetes. Methods The literature review was limited to randomized, controlled trials that included patients with diabetes. Only studies that measured major clinical end points were included. We defined four classes of clinical end points: all-cause mortality, cardiovascular mortality, major cardiovascular events (that is, myocardial infarction or stroke), and advanced microvascular outcomes (photocoagulation or visual loss, nephropathy or end-stage renal disease, neuropathy, or amputation). We separated the literature review into two categories. The first category evaluated the effects of hypertension control if the comparison examined an antihypertensive drug versus placebo or the effects of different target blood pressure levels. The second category evaluated the effects of different classes of drugs. We used several sources to identify the relevant literature. For older literature, we started with the Cochrane Collaboration Diabetes Group report on treatment of hypertension in diabetes, which was published in 1997 (19). This report has now been withdrawn because it is out of date, but it served as a reasonable starting point to identify pre-1997 literature. We then performed a MEDLINE search in May 2000 and updated it in April 2002. We used the keywords exp diabetes mellitus and exp hypertension[therapy or prevention and control] and limited the search to randomized, controlled trials. The final search produced 322 results. Of these, most were discarded because they did not measure major clinical outcomes, were observational in nature, were reviews or editorials, or did not primarily address the issue of treatment of hypertension. We then updated the search through consultation with experts and through examining references from meta-analyses and review articles. Data were extracted from the primary study reports by the primary author and were reviewed by the senior author. Accuracy and quality of the abstraction were confirmed through reabstraction and comparison with the original abstraction. The outcomes were broken into categories as described, and data on absolute and relative risk reduction and numbers needed to treat for benefit were derived from the primary reports or were calculated in standard fashion (20). Results Benefits of Blood Pressure Control The results of the studies of blood pressure control versus placebo, or of different blood pressure targets, are outlined in Table 1. The Systolic Hypertension in the Elderly Program (SHEP) enrolled a diabetes subgroup totaling 583 patients and randomly assigned these patients to chlorthalidone plus atenolol or reserpine versus placebo and usual care (21). The intensive group had a 9.8mm Hg decrease in systolic blood pressure and a 2.2mm Hg decrease in diastolic blood pressure, as well as a significant decline in total cardiovascular events and a nonsignificant trend for lower all-cause mortality. Table 1. Primary Trials of Hypertension Control in Diabetes The Systolic Hypertension in Europe (Syst-Eur) study (22) randomly assigned elderly patients ( 60 years of age) with systolic hypertension to nitrendipine or placebo. The mean decreases in systolic blood pressure and diastolic blood pressure were 8.6 and 3.9 mm Hg in the intervention group compared with the placebo group. In the subgroup of 492 patients with diabetes, this led to an improvement in the risk for cardiovascular death, all cardiovascular events, and stroke. There was no significant difference in overall mortality in unadjusted analyses; however, after adjustment for baseline differences between groups, there was a 55% reduction in overall mortality in the active treatment group (P = 0.04). The Heart Outcomes and Prevention Evaluation (HOPE) study evaluated the cardiovascular effects of the angiotensin-converting enzyme (ACE) inhibitor ramipril (23, 24). Patients with diabetes and at least one other cardiovascular risk factor (n = 3577) were randomly assigned to the ACE inhibitor ramipril or placebo. The participants had only mild elevations in systolic blood pressure at baseline, and blood pressure differences at the final visit were small (systolic blood pressure, 2.4 mm Hg lower; diastolic blood pressure, 1 mm Hg lower). The ramipril group had significantly lower risks for cardiovascular outcomes, total mortality, and microvascular diabetes complications. The lower cardiovascular risk persisted after adjustment for blood pressure differences, suggesting that ACE inhibitors may confer a benefit independent of blood pressure control. Furthermore, several smaller or short-term studies suggest that ACE inhibitors may have a renoprotective effect in patients with type 2 diabetes compared with placebo; this effect may be independent of blood pressure control and may occur regardless of whether albuminuria is present (25-32). Several studies have also evaluated the effectiveness of angiotensin II receptor blockers on outcomes in patients with type 2 diabetes. In the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study (33), 1513 participants with type 2 diabetes and nephropathy were randomly assigned to losartan or placebo. There were minimal differences in blood pressure. Losartan led to a reduction in the risk for the primary end point of combined doubling of the creatinine concentration, end-stage renal disease, or death; there was no difference in combined cardiovascular end points. The Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria (IPDM) Study (34) randomly assigned 590 hypertensive patients with type 2 diabetes and microalbuminuria to irbesartan, 300 mg or 150 mg daily, or placebo. There were small but significant reductions in systolic blood pressure with irbesartan. Compared with the placebo group, systolic blood pressure was 3 mm Hg lower in the 300-mg group and 2 mm Hg lower in the 150-mg group. The risk for overt nephropathy was 0.30 (95% CI, 0.14 to 0.61) in the 300-mg group and 0.61 (CI, 0.34 to 1.08) in the 150-mg group. In both RENAAL and IPDM, the differences in outcomes persisted after adjustment for blood pressure differences and baseline level of microalbuminuria, suggesting a benefit that is independent of systemic blood pressure. Several studies have specifically compared the effects of different blood pressure targets on diabetes outcomes. The Hypertension Optimal Treatment (HOT) study included a subgroup of 1501 patients with diabetes; participants were randomly assigned into three groups with target diastolic blood pressures of 90, 85, and 80 mm Hg (35). There were substantial improvements in diastolic blood pressure in these groups (20.3, 22.3, and 24.3 mm Hg, respectively, with achieved diastolic blood pressure of 85.2, 83.2, and 81.1 mm Hg). In patients with diabetes, the group randomly assigned to a diastolic blood pressure target of 80 mm Hg had a significantly reduced risk for cardiovascular death and major cardiovascular events and a nonsignificant trend toward improved overall mortality compared with those who had a target diastolic blood pressure of 90 mm Hg. The United Kingdom Prospective Diabetes Study (UKPDS) of hypertension randomly assigned 1148 patients with newly diagnosed type 2 diabetes to a less tight target blood pressure of 180/105 mm Hg or to a tight control target of 150/85 mm Hg (36). The achieved blood pressure was 154/87 mm Hg in the less tight control group and 144/82 mm Hg in the tight control group. In the tight control group, there were substantial reductions in risk for any diabetes end point, deaths related to diabetes, and stroke but a nonsignificant change in all-cause mortality. There was also a significant reduction in risk for microvascular disease, most of which was due to reduction in retinal photocoagulation. I

Examining the Evidence: A Systematic Review of the Inclusion and Analysis of Older Adults in Randomized Controlled Trials

ABSTRACTBACKGROUNDDue to a shortage of studies focusing on older adults, clinicians and policy makers frequently rely on clinical trials of the general population to provide supportive evidence for treating complex, older patients.OBJECTIVESTo examine the inclusion and analysis of complex, older adults in randomized controlled trials.REVIEW METHODSA PubMed search identified phase III or IV randomized controlled trials published in 2007 in JAMA, NEJM, Lancet, Circulation, and BMJ. Therapeutic interventions that assessed major morbidity or mortality in adults were included. For each study, age eligibility, average age of study population, primary and secondary outcomes, exclusion criteria, and the frequency, characteristics, and methodology of age-specific subgroup analyses were reviewed.RESULTSOf the 109 clinical trials reviewed in full, 22 (20.2%) excluded patients above a specified age. Almost half (45.6%) of the remaining trials excluded individuals using criteria that could disproportionately impact older adults. Only one in four trials (26.6%) examined outcomes that are considered highly relevant to older adults, such as health status or quality of life. Of the 42 (38.5%) trials that performed an age-specific subgroup analysis, fewer than half examined potential confounders of differential treatment effects by age, such as comorbidities or risk of primary outcome. Trials with age-specific subgroup analyses were more likely than those without to be multicenter trials (97.6% vs. 79.1%, p < 0.01) and funded by industry (83.3% vs. 62.7%, p < 0.05). Differential benefit by age was found in seven trials (16.7%).CONCLUSIONClinical trial evidence guiding treatment of complex, older adults could be improved by eliminating upper age limits for study inclusion, by reducing the use of eligibility criteria that disproportionately affect multimorbid older patients, by evaluating outcomes that are highly relevant to older individuals, and by encouraging adherence to recommended analytic methods for evaluating differential treatment effects by age.

Estimated Benefits of Glycemic Control in Microvascular Complications in Type 2 Diabetes

Blindness and renal failure are two of the most feared complications of diabetes. These devastating outcomes frequently result from insidious progression of abnormalities in small blood vessels (microvascular disease) over many years. Although microvascular disease is associated with the level of glycemic control [1-3], the Diabetes Control and Complications Trial (DCCT) was the first study to convincingly show that in patients with type 1 diabetes, improved glycemic control can reduce the risk for early microvascular complications [4]. The DCCT settled many issues, but it also raised difficult questions about the management of diabetes. There is now nearly uniform agreement that intensive glycemic control should be attempted for most patients with type 1 diabetes. However, the implications of the DCCT for the treatment of type 2 diabetes remain controversial [5-8]. Cohort studies suggest that early microvascular disease is related to hemoglobin A1c level in both type 1 and type 2 diabetes [3, 9], but the incidence of end-stage complications is much lower in type 2 diabetes [10, 11], presumably because of the older age at onset and competing risks for death. Thus, the benefits of intensive therapy in type 2 diabetes seem less compelling. The perceived difficulty of treating patients with type 2 diabetes, the potential harms related to macrovascular complications, and concern about hypoglycemia further fuel the controversy. These concerns are important because roughly 90% of diabetic patients have type 2 disease. Although long-term benefit may result from improved glycemic control, economic costs may be increased [12]. For many patients, insulin injections, frequent laboratory monitoring, increased office visits, more restrictive diets, and intensive at-home monitoring of glucose levels are required. Thus, it is critical that the possible long-term benefits of aggressive glycemic control in type 2 diabetes be better quantified [7, 13]. Such information may facilitate the counseling of patients and could help health care systems prioritize and focus costly clinical interventions. We therefore created a model to calculate the risks for developing blindness and end-stage renal disease for patients at different ages of diabetes onset and levels of glycemic control. The base-case analysis used data from the DCCT for rates of early disease [4, 14] and used cohort data from patients with type 2 diabetes for rates of subsequent progression to end-stage disease [10, 11, 15, 16]. Methods Markov Model A Markov model was constructed to analyze the risk for retinopathy and nephropathy in patients with type 2 diabetes. The structure of the model is shown in the (Figure 1). Estimates for the two complications were modeled separately so that they were assumed not to interact. The simulated patients progressed sequentially through increasingly severe disease states; death could occur in any disease state (Figure 1). Incidence and progression of retinopathy were defined as in the DCCT [4, 17]. Blindness was defined as corrected visual acuity of 20/200 or worse and was restricted to blindness caused by retinopathy or its sequelae (for example, macular edema). Microalbuminuria was defined as an albumin level of 30 to 300 mg/g of creatinine, proteinuria was defined as a protein level greater than 300 mg/g of creatinine, and end-stage renal disease was defined as renal disease that required dialysis or transplantation. Figure 1. Structure of the model. Amputation was not modeled because of a lack of evidence on the relative contributions of microvascular and macrovascular disease to the risk for amputation. Moreover, the same patients who were identified in our analyses as being at high risk for retinal and renal complications (and who therefore will benefit more from intensified glycemic control) will have a similarly high risk for neuropathy and its associated outcomes [18]. Our study addressed clinical risks and benefits associated with glycemic control and did not directly evaluate costs. The costs of decreasing hemoglobin A1c levels are not well defined for patients with type 2 diabetes because glucose control can be improved by many methods. Each method has different implications for the costs to the patient, payers, and society. However, we present results in the form of expectation functions so that if the costs and effectiveness of a specific intervention are known, estimates of the cost per complication prevented can be calculated from our tables. Assumptions The construction of the model was based on the states defined in the DCCT, which provided estimates for the rates of early microvascular disease. Our review of the literature and input from diabetes experts consistently identified the Rochester, Minnesota, cohort study of diabetic patients and the Wisconsin Epidemiologic Study of Diabetic Retinopathy [3, 9-11, 15] as the best studies with which to provide estimates of the rates of progression to end-stage outcomes; thus, these studies were used in the base-case analysis. Further literature was identified by searching the MEDLINE database search with the keyword diabetes, cross-referenced with retinopathy, blindness, visual loss, nephropathy, kidney disease and failure, renal disease and failure, blood glucose, glycemic control, mortality, and hemoglobin A1c. We reviewed the abstracts of the identified articles and obtained the articles that were relevant to the model structure. Additional literature was identified by review of references in these articles and through discussion with national experts in the field. Patients were assumed to have no clinically detectable microvascular complications at the time of diagnosis of diabetes. Although up to 20% of patients have retinopathy at the time of diagnosis [19], we excluded this subgroup because data on the distribution of these patients across hemoglobin A1c levels are lacking. In addition, patients who present with complications have already declared themselves to be at high risk and thus should be considered for intensive control. We assumed that incidence and early progression of retinopathy and development of microalbuminuria were related to level of glycemic control at the rates of progression shown in the DCCT [4, 14]. Each 10% increase in hemoglobin A1c level is accompanied by a 20% increase in the rate of developing microalbuminuria, a 56% increase in the rate of developing retinopathy, and a 64% increase in the rate of progression of retinopathy [14]. Further progression (to renal disease beyond microalbuminuria and from retinopathy to blindness) was assumed not to be related to level of glycemic control [20-25]. Data for sensitivity analyses were derived from the 95% CIs in the DCCT and the range of estimates available in the literature (Table 1). Table 1. Model Components for the Base-Case and Sensitivity Analyses: Annual Rates of Transition between Disease States* Mortality estimates were based on U.S. data from the Department of Vital Statistics [40]. These estimates were modified to reflect the higher mortality rates in patients with type 2 diabetes [41-47]. Mortality was not adjusted for level of glycemic control. Some cohort studies show a relation between level of glycemic control and mortality, but it is not clear whether a causal relation exists [48]. Nephropathy, even at early stages, has been reported to be associated with increased rates of death, particularly death from cardiovascular disease [37, 49-52]. Much of this association may be due to confounding, but the effect persists after adjustment according to available severity and comorbidity measures [50]. The base-case model assumes that early nephropathy does not increase mortality rates. However, to evaluate the potential importance of this factor, we compared the mortality benefits of improved glycemic control by using half of or the full observed association between early renal disease and increased mortality rates. Model Structure and Implementation The model was run independently for each age of diabetes onset and level of glycemic control and was implemented by creating matrices of the probabilities of going from one health state to the next during a 1-year period (Figure 1). The percentage of patients developing each level of complication was tabulated annually, continuing through 90 years of age. Mortality rates were updated at 5-year intervals. This technique represents a standard implementation of a nonstationary Markov process [53, 54]. Average life expectancy was calculated by multiplying the proportion of patients dying during each year by the total number of years survived. Average time spent in each disease state was determined by dividing the total time spent in a state by the number of patients who develop that state. All calculations and modeling were performed by using Stata for Windows (Stata Corp., College Station, Texas). Sensitivity analyses were conducted by using varying estimates at all transition points (Table 1) [54]. We included the full range of estimates in the literature in one-way sensitivity analyses. However, because some studies had extreme values for the transition probabilities (most likely because of small sample sizes or atypical patient populations), three-way sensitivity analyses were conducted by using the midpoint between the base-case and extreme estimates. We also tested the validity of the model by modifying the simulated patients to fit the characteristics of the populations of various actual studies of natural history (for example, the mean values for age, hemoglobin A1c level, and initial prevalence of disease found in these studies were used to generate a limited set of results) and by comparing the predictions of the model (within one-way sensitivity analysis range) with the observed values from these studies. Using the model predictions and the characteristics of a population of patients with type 2 diabetes at a large staff-model health ma

Duration of resuscitation efforts and survival after in-hospital cardiac arrest: an observational study

BACKGROUND During in-hospital cardiac arrests, how long resuscitation attempts should be continued before termination of efforts is unknown. We investigated whether duration of resuscitation attempts varies between hospitals and whether patients at hospitals that attempt resuscitation for longer have higher survival rates than do those at hospitals with shorter durations of resuscitation efforts. METHODS Between 2000 and 2008, we identified 64,339 patients with cardiac arrests at 435 US hospitals within the Get With The Guidelines—Resuscitation registry. For each hospital, we calculated the median duration of resuscitation before termination of efforts in non-survivors as a measure of the hospitals overall tendency for longer attempts. We used multilevel regression models to assess the association between the length of resuscitation attempts and risk-adjusted survival. Our primary endpoints were immediate survival with return of spontaneous circulation during cardiac arrest and survival to hospital discharge. FINDINGS 31,198 of 64,339 (48·5%) patients achieved return of spontaneous circulation and 9912 (15·4%) survived to discharge. For patients achieving return of spontaneous circulation, the median duration of resuscitation was 12 min (IQR 6-21) compared with 20 min (14-30) for non-survivors. Compared with patients at hospitals in the quartile with the shortest median resuscitation attempts in non-survivors (16 min [IQR 15-17]), those at hospitals in the quartile with the longest attempts (25 min [25-28]) had a higher likelihood of return of spontaneous circulation (adjusted risk ratio 1·12, 95% CI 1·06-1·18; p<0·0001) and survival to discharge (1·12, 1·02-1·23; 0·021). INTERPRETATION Duration of resuscitation attempts varies between hospitals. Although we cannot define an optimum duration for resuscitation attempts on the basis of these observational data, our findings suggest that efforts to systematically increase the duration of resuscitation could improve survival in this high-risk population. FUNDING American Heart Association, Robert Wood Johnson Foundation Clinical Scholars Program, and the National Institutes of Health.