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BACKGROUND: Polypharmacy and use of inappropriate medications have been linked to increased risk of falls, hospitalizations, cognitive impairment, and death. The primary objective of this review was to evaluate the effectiveness, comparative effectiveness, and harms of deprescribing interventions among community-dwelling older adults. METHODS: We searched OVID MEDLINE Embase, CINAHL, and the Cochrane Library from 1990 through February 2019 for controlled clinical trials comparing any deprescribing intervention to usual care or another intervention. Primary outcomes were all-cause mortality, hospitalizations, health-related quality of life, and falls. The secondary outcome was use of potentially inappropriate medications (PIMs). Interventions were categorized as comprehensive medication review, educational initiatives, and computerized decision support. Data abstracted by one investigator were verified by another. We used the Cochrane criteria to rate risk of bias for each study and the GRADE system to determine certainty of evidence (COE) for primary outcomes. RESULTS: Thirty-eight low and medium risk of bias clinical trials were included. Comprehensive medication review may have reduced all-cause mortality (OR 0.74, 95% CI: 0.58 to 0.95, I(2) = 0, k = 12, low COE) but probably had little to no effect on falls, health-related quality of life, or hospitalizations (low to moderate COE). Nine of thirteen trials reported fewer PIMs in the intervention group. Educational interventions probably had little to no effect on all-cause mortality, hospitalizations, or health-related quality of life (low to moderate COE). The effect on falls was uncertain (very low COE). All 11 education trials that included PIMs reported fewer in the intervention than in the control groups. Two of 4 computerized decision support trials reported fewer PIMs in the intervention arms; none included any primary outcomes. DISCUSSION: In community-dwelling people aged 65 years and older, medication deprescribing interventions may provide small reductions in mortality and use of potentially inappropriate medications. REGISTRY INFORMATION: PROSPERO - CRD42019132420. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11606-020-06089-2) contains supplementary material, which is available to authorized users.

BACKGROUND Inappropriate use of colorectal cancer (CRC) screening procedures can inflate healthcare costs and increase medical risk. Little is known about the prevalence or causes of inappropriate CRC screening.

Assessing the integrity of research climates and sharing such information with research leaders may support research best practices. We report here results of a pilot trial testing the effectiveness of a reporting and feedback intervention using the Survey of Organizational Research Climate (SOuRCe).We randomized 41 Veterans Health Administration (VA) facilities to a phone-based intervention designed to help research leaders understand their survey results (enhanced arm) or to an intervention in which results were simply distributed to research leaders (basic arm). Primary outcomes were (1) whether leaders took action, (2) whether actions taken were consistent with the feedback received, and (3) whether responses differed by receptivity to quality improvement input.Research leaders from 25 of 42 (59%) VA facilities consented to participate in the study intervention and follow-up, of which 14 were at facilities randomized to the enhanced arm. We completed follow-up interviews with 21 of the 25 leaders (88%), 12 from enhanced arm facilities. While not statistically significant, the proportion of leaders reporting taking some action in response to the feedback was twice as high in the enhanced arm than in the basic arm (67% vs. 33%, p = .20). While also not statistically significant, a higher proportion of actions taken among facilities in the enhanced arm were responsive to the survey results than in the basic arm (42% vs. 22%, p = .64).Enhanced feedback of survey results appears to be a promising intervention that may increase the likelihood of responsive action to improve organizational climates. Due to the small sample size of this pilot study, even large percentage-point differences between study arms are not statistically distinguishable. This hypothesis should be tested in a larger trial.

BACKGROUND Although benefits of performance measurement (PM) systems have been well documented, there is little research on negative unintended consequences of performance measurement systems in primary care. To optimize PM systems, a better understanding is needed of the types of negative unintended consequences that occur and of their causal antecedents.

Objective— Lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ), a proinflammatory enzyme that predominantly circulates with low-density lipoprotein (LDL), has been shown in general populations to predict cardiovascular (CV) events. We sought to determine whether increased Lp-PLA 2 would also predict CV events in the absence of high LDL-cholesterol (LDL-C), in a population with low high-density lipoprotein-cholesterol (HDL-C). Methods and Results— Plasma Lp-PLA 2 activity was measured at baseline and after 6 months on-trial in 1451 men with low HDL-C (mean, 32 mg/dL) and low LDL-C (mean 110 mg/dL), randomized to either placebo or gemfibrozil therapy in the Veterans Affairs HDL Intervention Trial (VA-HIT). Over a quartile range of increasing Lp-PLA 2 there was a significant increase in LDL-C and decrease in HDL-C ( P P =0.03 for trend). In Cox models, adjusted for major CV risk factors, a 1-SD increase in Lp-PLA 2 was associated with a significant increase in CV events (hazard ratio [HR] 1.17 95% CI 1.04 to 1.32). Although gemfibrozil reduced Lp-PLA 2 only modestly (6.6%), at higher levels of Lp-PLA 2 gemfibrozil produced a significant reduction in CV events. Conclusions— In VA-HIT, a population with low HDL-C and LDL-C, high Lp-PLA 2 independently predicted CV events that were reduced by gemfibrozil.

The significant cardiovascular disease (CVD) event reduction in the Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT) could not be fully explained by the 6% increase in high-density lipoprotein (HDL) cholesterol with the fibrate gemfibrozil. We examined whether measurement of HDL subpopulations provided additional information relative to CVD risk reduction. The HDL subpopulations were characterized by 2-dimensional gel electrophoresis in subjects who were treated with gemfibrozil (n = 754) or placebo (n = 741). In this study, samples obtained at the 3-month visit were used; and data were analyzed prospectively using CVD events (coronary heart disease death, myocardial infarction, or stroke) during the 5.1 years of follow-up. Analyses in the gemfibrozil arm showed that subjects with recurrent CVD events had significantly higher prebeta-1 and had significantly lower alpha-1 and alpha-2 HDL levels than those without such events. Prebeta-1 level was a significant positive predictor; alpha-1 and alpha-2 levels were significant negative risk factors for future CVD events. alpha-2 level was superior to HDL cholesterol level in CVD-risk assessment after adjustment for established risk factors. Gemfibrozil treatment was associated with 3% to 6% decreases in the small, lipid-poor prebeta-1 HDL and in the large, lipid-rich alpha-1 and alpha-2 HDL and with increases in the small alpha-3 (3%) and prealpha-3 (16%) HDLs. Although the use of gemfibrozil has been associated with reduction in CVD events in VA-HIT, HDL subpopulation analysis indicates that gemfibrozil-mediated improvement in CVD risk might not be the result of its effects on HDL. It is quite possible that much of the cardiovascular benefits of gemfibrozil are due to a much wider spectrum of effects on metabolic processes that is not reflected by changes in blood lipids and HDL subpopulations.

Cardiac troponin I (cTnI) measured after heart surgery has been associated with operative mortality. We sought to determine whether measuring cTnI after heart surgery provides additional prognostic information beyond that provided by validated preoperative risk scores, the Veterans Affairs (VA) risk score and the European System for Cardiac Operative Risk Evaluation (EuroSCORE).We retrospectively collected cTnI levels measured 24 hours after surgery in 1,186 patients who underwent coronary artery bypass graft surgery (n = 696) or valve surgery (n = 490). The outcomes were operative death and perioperative myocardial infarction. The ability of the cTnI and the risk scores to discriminate patients who did or did not have the study outcomes was assessed by the area under the receiver operating curve (c-index).Mean age was 66 +/- 10 years. Median cTnI was 38 ng/mL after valve surgery versus 18 ng/mL after coronary artery bypass graft surgery (p0.0001). There were 51 operative deaths (4.3%) and 142 perioperative myocardial infarctions (12%). For every 50 ng/mL increase in cTnI, the odds of operative death increased by 40% (odds ratio, 1.4; 95% confidence interval: 1.2 to 1.6) after coronary artery bypass graft surgery and by 30% (odds ratio, 1.3; 95% confidence interval: 1.1 to 1.5) after valve surgery. Cardiac troponin I was a significant independent correlate of perioperative myocardial infarction and death (p0.0001) with a c-index of 0.70 for death. Addition of cTnI improved the c-indexes of the risk scores for predicting death (from 0.75 to 0.79 for the VA risk score; p = 0.1; and from 0.69 to 0.77 for the EuroSCORE; p = 0.005).Postoperative cTnI measured 24 hours after heart surgery is independently associated with operative death and perioperative myocardial infarction and improves the ability to predict operative mortality in comparison with preoperative risk scores alone.

Background In service to its core mission of improving the health and well-being of veterans, Veterans Affairs (VA) leadership is committed to supporting research best practices in the VA. Recognizing that the behavior of researchers is influenced by the organizational climates in which they work, efforts to assess the integrity of research climates and share such information with research leadership in VA may be one way to support research best practices. The Survey of Organizational Research Climate (SOuRCe) is the first validated survey instrument specifically designed to assess the organizational climate of research integrity in academic research organizations. The current study reports on an initiative to use the SOuRCe in VA facilities to characterize the organizational research climates and pilot test the effectiveness of using SOuRCe data as a reporting and feedback intervention tool. Methods We administered the SOuRCe using a cross-sectional, online survey, with mailed follow-up to non-responders, of research-engaged employees in the research services of a random selection of 42 VA facilities (e.g., Hospitals/Stations) believed to employ 20 or more research staff. We attained a 51% participation rate, yielding more than 5,200 usable surveys. Results We found a general consistency in organizational research climates across a variety of sub-groups in this random sample of research services in the VA. We also observed similar SOuRCe scale score means, relative rankings of these scales and their internal reliability, in this VA-based sample as we have previously documented in more traditional academic research settings. Results also showed more substantial variability in research climate scores within than between facilities in the VA research service as reflected in meaningful subgroup differences. These findings suggest that the SOuRCe is suitable as an instrument for assessing the research integrity climates in VA and that the tool has similar patterns of results that have been observed in more traditional academic research settings. Conclusions The local and specific nature of organizational climates in VA research services, as reflected in variability across sub-groups within individual facilities, has important policy implications. Global, “one-size-fits-all” type initiatives are not likely to yield as much benefit as efforts targeted to specific organizational units or sub-groups and tailored to the specific strengths and weaknesses documented in those locations.

Background: Recent clinical trials indicate that treatment with lipid modifying therapy improves outcomes in patients with ischemic heart disease (IHD) and low levels of high density lipoprotein (HDL) cholesterol. The results of these trials, however, have not been widely implemented in clinical practice. Objectives: To develop and test an intervention designed to increase the rate of prescription of lipid modifying therapy and to determine the relative effectiveness of three different prompts (progress notes, patient letters, or computer chart reminders). Methods: The study was conducted in 11 US Department of Veterans Affairs Medical Centers. The effect of the intervention on the proportion of eligible patients receiving lipid modifying therapy was compared between five intervention sites and six matched control sites using a controlled before and after study design. Additionally, 92 providers within the intervention clinics were randomized to receive one of the three prompts. Data were analyzed using logistic regression modeling which incorporated terms to account for the clustered nature of the data. Results: At the intervention sites the prescription rate increased from 8.3% during the pre-intervention period to 39.1% during the intervention (OR = 6.5, 95% CI 5.2 to 8.2, p

Our goal was to further define the role of LPL gene polymorphisms in coronary heart disease (CHD) risk. We determined the frequencies of three LPL polymorphisms (D9N, N291S, and S447X) in 899 men from the Veterans Affairs HDL Intervention Trial (VA-HIT), a study that examined the potential benefits of increasing HDL with gemfibrozil in men with established CHD and low high density lipoprotein cholesterol (HDL-C; ≤40 mg/dl), and compared them with those of men without CHD from the Framingham Offspring Study (FOS). In VA-HIT, genotype frequencies for LPL D9N, N291S, and S447X were 5.3, 4.5, and 13.0%, respectively. These values differed from those for men in FOS having an HDL-C of >40, who had corresponding values of 3.2% (P = 0.06), 1.5% (P < 0.01), and 18.2% (P < 0.01). On gemfibrozil, carriers of the LPL N9 allele in VA-HIT had lower levels of large LDL (−32%; P < 0.01) but higher levels of small, dense LDL (+59%; P < 0.003) than did noncarriers. Consequently, mean LDL particle diameter was smaller in LPL N9 carriers than in noncarriers (20.14 ± 0.87 vs. 20.63 ± 0.80 nm; P < 0.003).In men with low HDL-C and CHD: 1) the LPL N9 and S291 alleles are more frequent than in CHD-free men with normal HDL-C, whereas the X447 allele is less frequent, and 2) the LPL N9 allele is associated with the LDL subclass response to gemfibrozil.

Gemfibrozil for secondary prevention of cardiovascular events in mild to moderate chronic renal insufficiency. Background Although cardiovascular disease and low high-density lipoprotein (HDL) cholesterol are common in people with renal insufficiency, data addressing the cardiovascular benefits of fibric acid derivatives in this population are sparse. We conducted a post hoc subgroup analysis of a randomized double-blind, placebo-controlled trial to determine whether gemfibrozil is effective and safe for secondary prevention of cardiovascular events in individuals with chronic renal insufficiency (CRI). Methods Using an analysis plan that was developed a priori, we analyzed data from the Veterans' Affairs High-Density Lipoprotein Intervention Trial (VA-HIT) study; a randomized trial of gemfibrozil versus placebo in 2531 men with established coronary disease, an HDL cholesterol level of 40 mg/dL (1.0 mmol/L) or less, and a low-density lipoprotein (LDL) cholesterol level of 140 mg/dL (3.6 mmol/L) or less. Of these, 1046 men had CRI as defined by creatinine clearance ≤75 mL/min using the Cockcroft-Gault equation, 99.8% of whom had either mild or moderate renal impairment (creatinine clearance 60–75 or 30–59.9 mL/min, respectively). Results The incidence of the primary outcome (coronary death or nonfatal myocardial infarction) was lower in participants with CRI who received gemfibrozil compared to placebo [hazard ratio (HR) 0.73; 95% CI 0.56–0.96, P = 0.02). The cmulative incidence of the primary end point was reduced from 24.3% to 18.2%. In subjects with CRI, gemfibrozil also significantly reduced the risk of the combined outcome of coronary death, nonfatal myocardial infarction, or stroke (HR 0.74, 95% CI 0.58–0.95, P = 0.02), but not the need for coronary revascularization (HR 0.85, 95% CI 0.66–1.10, P = 0.21) or total mortality (HR 1.03, 95% CI 0.78–1.35, P = 0.85). The overall incidence of adverse effects was similar in individuals receiving gemfibrozil and placebo. However, the risk of sustained increases in serum creatinine was increased in gemfibrozil recipients compared with placebo (5.9 vs. 2.8%, P = 0.02). Conclusion Gemfibrozil appears effective for secondary prevention of cardiovascular events in individuals with mild to moderate chronic renal insufficiency and HDL cholesterol of 40 mg/dL or less. However, the benefit and safety of gemfibrozil in people with more severe impairment of kidney function requires further study.

The American College of Chest Physicians provides recommendations for the use of anticoagulant medications for several indications that are important in the primary care setting. Warfarin, a vitamin K antagonist, is recommended for the treatment of venous thromboembolism and for the prevention of stroke in persons with atrial fibrillation, atrial flutter, or valvular heart disease. When warfarin therapy is initiated for venous thromboembolism, it should be given the first day, along with a heparin product or fondaparinux. The heparin product or fondaparinux should be continued for at least five days and until the patient's international normalized ratio is at least 2.0 for two consecutive days. The international normalized ratio goal and duration of treatment with warfarin vary depending on indication and risk. Warfarin therapy should be stopped five days before major surgery and restarted 12 to 24 hours postoperatively. Bridging with low-molecular-weight heparin or other agents is based on balancing the risk of thromboembolism with the risk of bleeding. Increasingly, self-testing is an option for selected patients on warfarin therapy. The ninth edition of the American College of Chest Physicians guidelines, published in 2012, includes a discussion of anticoagulants that have gained approval from the U.S. Food and Drug Administration since publication of the eighth edition in 2008. Dabigatran and apixaban are indicated for the prevention of systemic embolism and stroke in persons with nonvalvular atrial fibrillation. Rivaroxaban is indicated for the prevention of deep venous thrombosis in patients undergoing knee or hip replacement surgery, for treatment of deep venous thrombosis and pulmonary embolism, for reducing the risk of recurrent deep venous thrombosis and pulmonary embolism after initial treatment, and for prevention of systemic embolism in patients with nonvalvular atrial fibrillation.

Determine the viable yield of screening electronic Veterans Health Administration (VHA) records to identify patients who stop taking a long-term medication for reasons that might be addressed by healthcare providers.Prospectively screened cohort with mailed follow-up of positive screens.Electronic healthcare records were screened to identify patients receiving care in a Veterans Administration (VA) Health Care System who became past due for resupply of medication (statin) prescribed to reduce cholesterol and risks of adverse cardiovascular events. Subsequently, administrative data were used to classify and characterize patients as true or false positive screens. A follow-up survey mailed to the first 1000 positive screens asked them if they were still taking a statin provided by the VHA, and if not, why?From February to July 2010, 1000 (4.6%) of the statin-recipient cohort of 21,935 became past due for a resupply. Subsequently 824 (3.8%; 95% confidence interval [CI] 3.5%-4.0%) were classified as true positives (positive predictive value 82%; 95% CI 80%-85%), and 176 (0.8%; 95% CI 0.7%-0.9%) as false positives. However, the 824 true positives included 95 deceased, 17 long-term care residents, 302 who reported good reasons for no longer getting the statin, and 208 who eventually got another supply. The overall yield of good candidates for efforts to reinstate long-term use of statins was only 20%.The viable yield from electronically screening VA healthcare records to find patients who stopped taking statins was low. More complete records and sophisticated screening programs are needed to improve the yield.

The effect of disease management for chronic obstructive pulmonary disease (COPD) is not well established.To determine whether a simplified disease management program reduces hospital admissions and emergency department (ED) visits due to COPD.We performed a randomized, adjudicator-blinded, controlled, 1-year trial at five Veterans Affairs medical centers of 743 patients with severe COPD and one or more of the following during the previous year: hospital admission or ED visit for COPD, chronic home oxygen use, or course of systemic corticosteroids for COPD. Control group patients received usual care. Intervention group patients received a single 1- to 1.5-hour education session, an action plan for self-treatment of exacerbations, and monthly follow-up calls from a case manager.We determined the combined number of COPD-related hospitalizations and ED visits per patient. Secondary outcomes included hospitalizations and ED visits for all causes, respiratory medication use, mortality, and change in Saint George's Respiratory Questionnaire. After 1 year, the mean cumulative frequency of COPD-related hospitalizations and ED visits was 0.82 per patient in usual care and 0.48 per patient in disease management (difference, 0.34; 95% confidence interval, 0.15-0.52; P0.001). Disease management reduced hospitalizations for cardiac or pulmonary conditions other than COPD by 49%, hospitalizations for all causes by 28%, and ED visits for all causes by 27% (P0.05 for all).A relatively simple disease management program reduced hospitalizations and ED visits for COPD. Clinical trial registered with www.clinicaltrials.gov (NCT00126776).

Background Previous studies on the effects of Statins in preventing atrial fibrillation (AF) after cardiac surgery have shown conflicting results. Whether statins prevent AF in patients treated with postoperative beta blockers and whether the statin-effect is dose related are unknown. Methods We retrospectively studied 1936 consecutive patients who underwent coronary artery bypass graft (CABG) (n = 1493) or valve surgery (n = 443) at the Minneapolis Veterans Affairs Medical Center. All patients were in sinus rhythm before the surgery. Postoperative beta blockers were administered routinely (92% within 24 hours postoperatively). Results Mean age was 66+10 years and 68% of the patients were taking Statins. Postoperative AF occurred in 588 (30%) patients and led to longer length of stay in the intensive care unit versus those without AF (5.1+7.6 days versus 2.5+2.3 days, p < 0.0001). Patients with a past history of AF had a 5 times higher risk of postoperative AF (odds ratio 5.1; 95% confidence interval 3.4 to 7.7; p < 0.0001). AF occurred in 31% of patients taking statins versus 29% of the others (p = 0.49). In multivariable analysis, statins were not associated with AF (odds ratio (OR) 0.93, 95% confidence interval (CI) 0.7 to 1.2; p = 0.59). However, in a subgroup analysis, the patients treated with Simvastatin >20 mg daily had a 36% reduction in the risk of postoperative AF (OR 0.64, 95% CI 0.43 to 0.6; p = 0.03) in comparison to those taking lower dosages. Conclusion Among cardiac surgery patients treated with postoperative beta blockers Statin treatment reduces the incidence of postoperative AF when used at higher dosages

Aims The aim of this study was to assess whether perioperative N -acetylcysteine (NAC), an antioxidant, prevents acute renal injury (ARI) after cardiac surgery. Methods and results We performed a systematic review of randomized controlled trials (RCTs) of NAC in adult cardiac surgery patients. The RCTs were identified by searching MEDLINE (1960–2008), clinicaltrials . gov website, and hand-searching references of relevant publications. Primary outcome was ARI (absolute increase >0.5 mg/dL or relative increase >25%, in serum creatinine from baseline within 5 days after surgery). Random effects model was used to perform a meta-analysis. Forest plots and I 2 test were used to assess heterogeneity among studies. Ten RCTs ( n = 1163 patients) were included. Mean age was 70 ± 7.4 years, 71% were male, and 66% underwent coronary artery bypass surgery. N -Acetylcysteine did not reduce ARI incidence [35% NAC vs. 37% placebo; relative risk (RR) 0.91, 95% CI 0.79–1.06, P = 0.24]. Overall, 3.3% of patients required haemodialysis (NAC vs. placebo; RR = 1.13, 95% CI 0.59–2.17) and 3% died (RR = 1.10, 95% CI 0.56–2.16). There was a trend towards reduced ARI incidence among patients with baseline chronic kidney disease assigned to intravenous NAC (RR = 0.80, 95% CI 0.64–1.01, P = 0.06). Conclusion This meta-analysis of RCTs showed that prophylactic perioperative NAC in cardiac surgery does not reduce ARI, haemodialysis, or death.

Heart rate (HR) profile during exercise predicts all-cause mortality. However, less is known about its relation to sudden (vs nonsudden) death in asymptomatic people. The relation of exercise HR parameters (HR at rest, target HR achievement, HR increase, and HR recovery) with sudden death, coronary heart disease (CHD) death, myocardial infarction, and all-cause mortality was assessed in 12,555 men who participated in MRFIT. Subjects were 35 to 57 years old without clinical CHD, but with higher than average Framingham risk. Trial follow-up was 7 years, and extended follow-up after the trial for all-cause mortality was 25 years. After adjusting for cardiac risk factors, having to stop exercise before achieving 85% of age-specific maximal HR was associated with increased risk of sudden death (hazard ratio 1.8, 95% confidence interval [CI] 1.3 to 2.5, p = 0.001), CHD death (hazard ratio 1.4, 95% CI 1.2 to 1.5, p

Background— Changes in conventional lipid risk factors with gemfibrozil treatment only partially explain the reductions in coronary heart disease (CHD) events experienced by men in the Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT). We examined whether measurement of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) particle subclasses provides additional information relative to CHD risk reduction. Methods and Results— This is a prospective nested case-control study of 364 men with a new CHD event (nonfatal myocardial infarction or cardiac death) during a 5.1-year (median) follow-up and 697 age-matched controls. Nuclear magnetic resonance (NMR) spectroscopy was used to quantify levels of LDL and HDL particle subclasses and mean particle sizes in plasma obtained at baseline and after 7 months of treatment with gemfibrozil or placebo. Odds ratios for a 1-SD increment of each lipoprotein variable were calculated with adjusted logistic regression models. Gemfibrozil treatment increased LDL size and lowered numbers of LDL particles (−5%) while raising numbers of HDL particles (10%) and small HDL subclass particles (21%). Concentrations of these LDL and HDL particles achieved with gemfibrozil were significant, independent predictors of new CHD events. For total LDL and HDL particles, odds ratios predicting CHD benefit were 1.28 (95% CI, 1.12 to 1.47) and 0.71 (95% CI, 0.61 to 0.81), respectively. Mean LDL and HDL particle sizes were not associated with CHD events. Conclusions— The effects of gemfibrozil on NMR-measured LDL and HDL particle subclasses, which are not reflected by conventional lipoprotein cholesterol measures, help to explain the demonstrated benefit of this therapy in patients with low HDL cholesterol.

Objective— To test the hypothesis whether determination of high-density lipoprotein (HDL) subpopulations provides more power to predict recurrent cardiovascular disease (CVD) events (nonfatal myocardial infarction, coronary heart disease death, and stroke) than traditional risk factors in the Veterans Affairs HDL Intervention Trial (VA-HIT). Methods and Results— Apolipoprotein A-I (apoA-I)–containing HDL subpopulations were quantitatively determined by nondenaturing 2D gel electrophoresis. Hazard ratios of recurrent CVD events were calculated by comparing VA-HIT subjects with (n=398) and without (n=1097) such events. Subjects with new CVD events had significantly lower HDL-C, apoA-I, and large cholesterol-rich HDL particle (α-1, α-2, pre–α-1, and pre–α-2) levels, significantly higher triglyceride, and small poorly lipidated HDL particle (pre–β-1 and α-3) levels than subjects without such events. Multivariate analyses indicated that α-1 and α-2 particle levels were significant negative risk factors, whereas α-3 level was a significant positive risk factor for new CVD events. Pre–β-1 level was a significant risk factor for new CVD events only in univariate analysis. A forward selection model indicated that α-1 was the most significant risk factor for recurrent CVD events among HDL particles. Conclusions— An altered HDL subpopulation profile marked with low α-1 and α-2 levels and a high α-3 level in coronary heart disease patients indicated an elevated risk for new CVD events. Moreover, α-1 and α-2 levels were superior to HDL-C levels in risk assessment in patients with low HDL-C in VA-HIT.

We conducted a meta-analysis of patients with coronary heart disease (CHD) to determine the effectiveness of statin therapy; whether effectiveness varied according to patient characteristics, outcomes, or pretreatment low-density lipoprotein cholesterol (LDL-C) levels; and the optimal LDL-C goal and the level at which to initiate statin therapy.Randomized trials or systematic reviews for secondary prevention of CHD with statin therapy published between January 1966 and December 2002 were identified through MEDLINE and the Cochrane Library. Studies were included if they randomly assigned adults with CHD to statin therapy or control, enrolled at least 100 individuals per arm, reported clinical outcomes and LDL-C levels, and were published as full studies in English. Two reviewers abstracted data using a prospectively designed protocol.Twenty-five studies enrolling 69 511 individuals were included. Participants in 19 placebo-controlled trials had a mean age of 63 years and a mean pretreatment LDL-C level of 149 mg/dL (3.85 mmol/L); 23% were women. Statin therapy reduced CHD mortality or nonfatal myocardial infarction 25% (relative risk [RR], 0.75; 95% confidence interval [CI], 0.71-0.79), all-cause mortality 16% (RR, 0.84; 95% CI, 0.79-0.89), and CHD mortality 23% (RR, 0.77; 95% CI, 0.71-0.83). Beneficial effects were seen in women and the elderly. There were no data to determine whether lowering the LDL-C level to less than 100 mg/dL (2.59 mmol/L) was superior to lowering it to 100 to 130 mg/dL (2.59-3.36 mmol/L). Meta-regression analyses revealed risk reductions for CHD mortality or nonfatal myocardial infarction and major vascular events across available pretreatment LDL-C levels.Statin therapy reduces mortality and morbidity in adults with CHD, even at pretreatment LDL-C levels as low as 100 mg/dL (2.59 mmol/L).