Deprescribing for Community-Dwelling Older Adults: a Systematic Review and Meta-analysis.

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, I2 = 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.

Effects on Health Outcomes of a Mediterranean Diet With No Restriction on Fat Intake: A Systematic Review and Meta-analysis.

BACKGROUND: Mediterranean diets may be healthier than typical Western diets. PURPOSE: To summarize the literature comparing a Mediterranean diet with unrestricted fat intake with other diets regarding their effects on health outcomes in adults. DATA SOURCES: Ovid MEDLINE, CINAHL, and the Cochrane Library from 1990 through April 2016. STUDY SELECTION: Controlled trials of 100 or more persons followed for at least 1 year for mortality, cardiovascular, hypertension, diabetes, and adherence outcomes, as well as cohort studies for cancer outcomes. DATA EXTRACTION: Data extracted by 1 investigator was verified by another. Two reviewers assessed risk of bias and strength of evidence. DATA SYNTHESIS: Two primary prevention trials found no difference in all-cause mortality between diet groups. One large primary prevention trial found that a Mediterranean diet resulted in a lower incidence of major cardiovascular events (hazard ratio [HR], 0.71 [95% CI, 0.56 to 0.90]), breast cancer (HR, 0.43 [CI, 0.21 to 0.88]), and diabetes (HR, 0.70 [CI, 0.54 to 0.92]). Pooled analyses of primary prevention cohort studies showed that compared with the lowest quantile, the highest quantile of adherence to a Mediterranean diet was associated with a reduction in total cancer mortality (risk ratio [RR], 0.86 [CI, 0.82 to 0.91]; 13 studies) and in the incidence of total (RR, 0.96 [CI, 0.95 to 0.97]; 3 studies) and colorectal (RR, 0.91 [CI, 0.84 to 0.98; 9 studies]) cancer. Of 3 secondary prevention studies reporting cardiovascular outcomes, 1 found a lower risk for recurrent myocardial infarction and cardiovascular death with the Mediterranean diet. There was inconsistent, minimal, or no evidence pertaining to any other outcome, including adherence, hypertension, cognitive function, kidney disease, rheumatoid arthritis, and quality of life. LIMITATIONS: Few trials; medium risk-of-bias ratings for many studies; low or insufficient strength of evidence for outcomes; heterogeneous diet definitions and components. CONCLUSION: Limited evidence suggests that a Mediterranean diet with no restriction on fat intake may reduce the incidence of cardiovascular events, breast cancer, and type 2 diabetes mellitus but may not affect all-cause mortality. PRIMARY FUNDING SOURCE: Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Quality Enhancement Research Initiative. (PROSPERO: CRD42015020262).

Rates and correlates of potentially inappropriate colorectal cancer screening in the Veterans Health Administration.

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. OBJECTIVE: Our aim was to estimate the prevalence of potentially inappropriate CRC screening, and its association with patient and facility characteristics in the Veterans Health Administration (VHA) . DESIGN AND PARTICIPANTS: We conducted a cross-sectional study of all VHA patients aged 50 years and older who completed a fecal occult blood test (FOBT) or a screening colonoscopy between 1 October 2009 and 31 December 2011 (n = 1,083,965). MAIN MEASURES: Measures included: proportion of patients whose test was classified as potentially inappropriate; associations between potentially inappropriate screening and patient demographic and health characteristics, facility complexity, CRC screening rates, dependence on FOBT, and CRC clinical reminder attributes. KEY RESULTS: Of 901,292 FOBT cases, 26.1 % were potentially inappropriate (13.9 % not due, 7.8 % limited life expectancy, 11.0 % receiving FOBT when colonoscopy was indicated). Of 134,335 screening colonoscopies, 14.2 % were potentially inappropriate (10.4 % not due, 4.4 % limited life expectancy). Each additional 10 years of patient age was associated with an increased likelihood of undergoing potentially inappropriate screening (ORs = 1.60 to 1.83 depending on screening mode). Compared to facilities scoring in the bottom third on a measure of reliance on FOBT (versus screening colonoscopy), facilities scoring in the top third were less likely to conduct potentially inappropriate FOBTs (OR = 0.,78) but more likely to conduct potentially inappropriate colonoscopies (OR = 2.20). Potentially inappropriate colonoscopies were less likely to be conducted at facilities where primary care providers were assigned partial responsibility (OR = 0.74) or full responsibility (OR = 0.73) for completing the CRC clinical reminder. CONCLUSIONS: A substantial number of VHA CRC screening tests are potentially inappropriate. Establishing processes that enforce appropriate screening intervals, triage patients with limited life expectancies, and discourage the use of FOBTs when a colonoscopy is indicated may reduce inappropriate testing.

Screening pelvic examinations in asymptomatic, average-risk adult women: an evidence report for a clinical practice guideline from the American College of Physicians.

BACKGROUND: Pelvic examination is often included in well-woman visits even when cervical cancer screening is not required. PURPOSE: To evaluate the diagnostic accuracy, benefits, and harms of pelvic examination in asymptomatic, nonpregnant, average-risk adult women. Cervical cancer screening was not included. DATA SOURCES: MEDLINE and Cochrane databases through January 2014 and reference lists from identified studies. STUDY SELECTION: 52 English-language studies, 32 of which included primary data. DATA EXTRACTION: Data were extracted on study and sample characteristics, interventions, and outcomes. Quality of the diagnostic accuracy studies was evaluated using a published instrument, and quality of the survey studies was evaluated with metrics assessing population representativeness, instrument development, and response rates. DATA SYNTHESIS: The positive predictive value of pelvic examination for detecting ovarian cancer was less than 4% in the 2 studies that reported this metric. No studies that investigated the morbidity or mortality benefits of screening pelvic examination for any condition were identified. The percentage of women reporting pelvic examination-related pain or discomfort ranged from 11% to 60% (median, 35%; 8 studies [n = 4576]). Corresponding figures for fear, embarrassment, or anxiety ranged from 10% to 80% (median, 34%; 7 studies [n = 10 702]). LIMITATION: Only English-language publications were included; the evidence on diagnostic accuracy, morbidity, and mortality was scant; and the studies reporting harms were generally low quality. CONCLUSION: No data supporting the use of pelvic examination in asymptomatic, average-risk women were found. Low-quality data suggest that pelvic examinations may cause pain, discomfort, fear, anxiety, or embarrassment in about 30% of women. PRIMARY FUNDING SOURCE: Department of Veterans Affairs.

Updated guidelines on outpatient anticoagulation.

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.

Unintended consequences of implementing a national performance measurement system into local practice.

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. OBJECTIVES: (1) Identify unintended negative consequences of PM systems for patients. (2) Develop a conceptual framework of hypothesized relationships between PM systems, facility-level variables (local implementation strategies, primary care staff attitudes and behaviors), and unintended negative effects on patients. DESIGN, PARTICIPANTS, APPROACH: Qualitative study design using dissimilar cases sampling. A series of 59 in-person individual semi-structured interviews at four Veterans Health Administration (VHA) facilities was conducted between February and July 2009. Participants included members of primary care staff and facility leaders. Sites were selected to assure variability in the number of veterans served and facility scores on national VHA performance measures. Interviews were recorded, transcribed and content coded to identify thematic categories and relationships. RESULTS: Participants noted both positive effects and negative unintended consequences of PM. We report three negative unintended consequences for patients. Performance measurement can (1) lead to inappropriate clinical care, (2) decrease provider focus on patient concerns and patient service, and (3) compromise patient education and autonomy. We also illustrate examples of negative consequences on primary care team dynamics. In many instances these problems originate from local implementation strategies developed in response to national PM definitions and policies. CONCLUSIONS: Facility-level strategies undertaken to implement national PM systems may result in inappropriate clinical care, can distract providers from patient concerns, and may have a negative effect on patient education and autonomy. Further research is needed to ascertain how features of centralized PM systems influence whether measures are translated locally by facilities into more or less patient-centered policies and processes.

Meta-analysis: effect of patient self-testing and self-management of long-term anticoagulation on major clinical outcomes.

BACKGROUND: Anticoagulation with vitamin K antagonists reduces major thromboembolic complications in at-risk patients. With portable monitoring devices, patients can conduct their own international normalized ratio testing and dose adjustment at home. PURPOSE: To determine whether patient self-testing (PST), alone or in combination with self-adjustment of doses (patient self-management [PSM]), is associated with a reduction in thromboembolic complications and all-cause mortality without an increase in major bleeding events compared with usual care. DATA SOURCES: MEDLINE and the Cochrane Central Register of Controlled Trials. STUDY SELECTION: Studies published in English from 1966 to October 2010 that enrolled outpatient adults receiving long-term (>3 months) oral anticoagulant therapy and that compared PST or PSM with care in a physician's office or an anticoagulation clinic were included. DATA EXTRACTION: Two investigators reviewed each article. Three investigators extracted data from articles that met inclusion criteria by using standardized data abstraction forms. Studies were assessed for quality, and the overall strength of evidence was rated for each clinical outcome. DATA SYNTHESIS: Twenty-two trials, with a total of 8413 patients, were included. In one half of the trials, fewer than 50% of potentially eligible persons successfully completed the training and agreed to be randomly assigned. Patients randomly assigned to PST or PSM had lower total mortality (Peto odds ratio [OR], 0.74 [95% CI, 0.63 to 0.87]), lower risk for major thromboembolism (Peto OR, 0.58 [CI, 0.45 to 0.75]), and no increased risk for a major bleeding event (Peto OR, 0.89 [CI, 0.75 to 1.05]). The strength of evidence was moderate for the bleeding and thromboembolism outcomes but low for mortality. Eight of 11 trials reported that patient satisfaction, quality of life, or both was better with PST or PSM than with usual care. LIMITATIONS: In one half of the trials, fewer than 50% of the potentially eligible patients were randomly assigned. Only 5 trials were considered high quality, and only 2 were conducted in the United States. No studies addressed whether PST or PSM is safe during the high-risk initiation phase. CONCLUSION: Compared with usual care, PST with or without PSM is associated with significantly fewer deaths and thromboembolic events, without increased risk for a serious bleeding event, for a highly selected group of motivated adult patients requiring long-term anticoagulation with vitamin K antagonists. Whether this care model is cost-effective and can be implemented successfully in typical U.S. health care settings requires further study. PRIMARY FUNDING SOURCE: U.S. Department of Veterans Affairs Health Services Research and Development Service.

Disease management program for chronic obstructive pulmonary disease: a randomized controlled trial.

RATIONALE: The effect of disease management for chronic obstructive pulmonary disease (COPD) is not well established. OBJECTIVES: To determine whether a simplified disease management program reduces hospital admissions and emergency department (ED) visits due to COPD. METHODS: 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. MEASUREMENTS AND MAIN RESULTS: 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; P < 0.001). 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% (P < 0.05 for all). CONCLUSIONS: A relatively simple disease management program reduced hospitalizations and ED visits for COPD. Clinical trial registered with www.clinicaltrials.gov (NCT00126776).

Efficacy of N-acetylcysteine in preventing renal injury after heart surgery: a systematic review of randomized trials.

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.

Efficacy of gemfibrozil in the primary prevention of atrial fibrillation in a large randomized controlled trial.

BACKGROUND: Peroxisome proliferator-activated receptor alpha (PPARalpha) activators reduce inflammation and oxidative stress. Inflammation plays an important role in the initiation and maintenance of atrial fibrillation (AF). It has been suggested that PPARalpha activators may have antiarrhythmic properties, but no clinical data exist. The objective of this study was to investigate whether the PPARalpha activator gemfibrozil prevents or delays the development of AF in patients with coronary heart disease. METHODS: We retrospectively analyzed the electrocardiograms (ECGs) performed in the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial, a multicenter, randomized, double-blinded, secondary prevention trial of gemfibrozil and matching placebo. The ECGs were performed annually or biannually and when clinically indicated. Participants who were in AF on baseline ECG were excluded from the present analysis. Relative risk for AF was calculated from Cox regression with death as a competing risk factor. RESULTS: A total of 12,605 ECGs from 2,130 participants were interpreted (5.9 +/- 2.1 ECGs per participant, range 2-20). At baseline, the gemfibrozil (n = 1,070) and placebo (n = 1,060) groups were well matched. Mean age was 64.1 +/- 7.1 years. Over 4.4 +/- 1.5 years of follow-up, 123 (5.8%) participants developed new AF. There was no difference in AF incidence between the gemfibrozil and placebo groups (64/1,070 vs 59/1,060, respectively; P = .33). In Cox regression, the risk of AF was similar between the 2 study groups (hazard ratio 1.04, 95% CI 0.73-1.49, P = .82). CONCLUSIONS: In this post hoc analysis of a multicenter, double-blinded, randomized controlled trial, the PPARalpha activator gemfibrozil did not reduce the 4-year incidence of AF among men with coronary heart disease.

Cardiovascular events with increased lipoprotein-associated phospholipase A(2) and low high-density lipoprotein-cholesterol: the Veterans Affairs HDL Intervention Trial.

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 < 0.0001), and an increased percentage of myocardial infarction (MI), stroke, or CHD death (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.

Utility of N-acetylcysteine to prevent acute kidney injury after cardiac surgery: a randomized controlled trial.

BACKGROUND: Acute kidney injury (AKI) after heart surgery is associated with increased mortality. We sought to determine whether prophylactic perioperative administration of N-acetylcysteine (NAC) prevents postoperative AKI in patients with chronic kidney disease undergoing cardiac surgery (clinical trials.gov identifier NCT00211653). METHODS: In this prospective, randomized, placebo-controlled, double-blinded clinical trial, 102 patients with chronic kidney disease who underwent heart surgery at the Minneapolis Veterans Affairs Medical Center were randomized to either NAC (n = 50) 600 mg PO twice daily or placebo (n = 52) for a total of 14 doses (3 preoperative). The primary outcome was maximum change in creatinine from baseline within 7 days after surgery. Secondary outcome was AKI (ie, >0.5 mg/dL or >or=25% increase in creatinine from baseline). RESULTS: Creatinine increased in both groups (0.45 +/- 0.7 mg/dL in NAC vs 0.55 +/- 0.9 mg/dL in placebo, P = .53) and peaked on postoperative day 5. Acute kidney injury occurred in 41 patients (22 NAC vs 19 placebo, P = .44) by postoperative day 5, but persisted in only 14 (7 NAC vs 7 placebo, P = .94) by day 30. In multivariable analysis, perioperative NAC was unassociated with AKI (relative risk 1.2, 95% CI, 0.8-1.9, P = .34). Five patients (3 NAC vs 2 placebo, P = .68) underwent hemodialysis, and 5 (2 NAC vs 3 placebo, P = 1.0) died perioperatively. There was no difference in lengths of stay in the intensive care unit (4.9 +/- 7 days in NAC vs 6.5 +/- 9 days in placebo, P = .06) and the hospital (13.2 +/- 13 days in NAC vs 16.7 +/- 17 days in placebo, P = .12). CONCLUSION: Prophylactic perioperative NAC administration does not prevent AKI after cardiac surgery.

Relation of heart rate parameters during exercise test to sudden death and all-cause mortality in asymptomatic men.

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 <0.001), and all-cause mortality (hazard ratio 1.3, 95% CI 1.2 to 1.4, p <0.001). Increased HR at rest (p = 0.001), attenuated HR increase (p = 0.02), delayed HR recovery (p = 0.04), and exercise duration (p <0.0001) were independent predictors of all-cause death in the overall study population and also in the subgroup that achieved target HR. In conclusion, middle-aged men without clinical CHD who stopped exercise before reaching 85% of maximal HR had a higher risk of sudden death. Other exercise HR parameters and exercise duration predicted all-cause mortality.

Relation of gemfibrozil treatment and high-density lipoprotein subpopulation profile with cardiovascular events in the Veterans Affairs High-Density Lipoprotein Intervention Trial.

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.