The influence of patient adherence on anticoagulation control with warfarin: results from the International Normalized Ratio Adherence and Genetics (IN-RANGE) Study.

BACKGROUND: Warfarin sodium is a highly efficacious drug, but proper levels of anticoagulation are difficult to maintain. Conflicting data exist on the influence of patient adherence on anticoagulation control. METHODS: We performed a prospective cohort study at 3 anticoagulation clinics to determine the effect of adherence on anticoagulation control. Patients treated with warfarin with a target international normalized ratio of 2.0 to 3.0 were monitored with electronic Medication Event Monitoring System (MEMS) medication bottle caps. Detailed information was collected on other factors that might alter warfarin response. RESULTS: Among 136 participants observed for a mean of 32 weeks, 92% had at least 1 missed or extra bottle opening; 36% missed more than 20% of their bottle openings; and 4% had more than 10% extra bottle openings. In multivariable analyses, there was a significant association between underadherence and underanticoagulation. For each 10% increase in missed pill bottle openings, there was a 14% increase in the odds of underanticoagulation (P<.001); participants with more than 20% missed bottle openings (1-2 missed days each week) had more than a 2-fold increase in the odds of underanticoagulation (adjusted odds ratio, 2.10; 95% confidence interval, 1.48-2.96). Participants who had extra pill bottle openings on more than 10% of days had a statistically significant increase in overanticoagulation (adjusted odds ratio, 1.73; 95% confidence interval, 1.09-2.74). CONCLUSION: Patients have substantial difficulties maintaining adequate adherence with warfarin regimens, and this poor adherence has a significant effect on anticoagulation control.

A low-carbohydrate as compared with a low-fat diet in severe obesity.

BACKGROUND: The effects of a carbohydrate-restricted diet on weight loss and risk factors for atherosclerosis have been incompletely assessed. METHODS: We randomly assigned 132 severely obese subjects (including 77 blacks and 23 women) with a mean body-mass index of 43 and a high prevalence of diabetes (39 percent) or the metabolic syndrome (43 percent) to a carbohydrate-restricted (low-carbohydrate) diet or a calorie- and fat-restricted (low-fat) diet. RESULTS: Seventy-nine subjects completed the six-month study. An analysis including all subjects, with the last observation carried forward for those who dropped out, showed that subjects on the low-carbohydrate diet lost more weight than those on the low-fat diet (mean [+/-SD], -5.8+/-8.6 kg vs. -1.9+/-4.2 kg; P=0.002) and had greater decreases in triglyceride levels (mean, -20+/-43 percent vs. -4+/-31 percent; P=0.001), irrespective of the use or nonuse of hypoglycemic or lipid-lowering medications. Insulin sensitivity, measured only in subjects without diabetes, also improved more among subjects on the low-carbohydrate diet (6+/-9 percent vs. -3+/-8 percent, P=0.01). The amount of weight lost (P<0.001) and assignment to the low-carbohydrate diet (P=0.01) were independent predictors of improvement in triglyceride levels and insulin sensitivity. CONCLUSIONS: Severely obese subjects with a high prevalence of diabetes or the metabolic syndrome lost more weight during six months on a carbohydrate-restricted diet than on a calorie- and fat-restricted diet, with a relative improvement in insulin sensitivity and triglyceride levels, even after adjustment for the amount of weight lost. This finding should be interpreted with caution, given the small magnitude of overall and between-group differences in weight loss in these markedly obese subjects and the short duration of the study. Future studies evaluating long-term cardiovascular outcomes are needed before a carbohydrate-restricted diet can be endorsed.

Adherence to warfarin assessed by electronic pill caps, clinician assessment, and patient reports: results from the IN-RANGE study.

BACKGROUND: Patient adherence to warfarin may influence anticoagulation control; yet, adherence among warfarin users has not been rigorously studied. OBJECTIVE: Our goal was to quantify warfarin adherence over time and to compare electronic medication event monitoring systems (MEMS) cap measurements with both self-report and clinician assessment of patient adherence. DESIGN: We performed a prospective cohort study of warfarin users at 3 Pennsylvania-based anticoagulation clinics and assessed pill-taking behaviors using MEMS caps, patient reports, and clinician assessments. RESULTS: Among 145 participants, the mean percent of days of nonadherence by MEMS was 21.8% (standard deviation+/-21.1%). Participants were about 6 times more likely to take too few pills than to take extra pills (18.8 vs. 3.3%). Adherence changed over time, initially worsening over the first 6 months of monitoring, which was followed by improvement beyond 6 months. Although clinicians were statistically better than chance at correctly labeling a participant's adherence (odds ratio = 2.05, p = 0.015), their estimates often did not correlate with MEMS-cap data; clinicians judged participants to be "adherent" at 82.8% of visits that were categorized as moderately nonadherent using MEMS-cap data (>or=20% nonadherence days). Similarly, at visits when participants were moderately nonadherent by MEMS, they self-reported perfect adherence 77.9% of the time. CONCLUSIONS: These results suggest that patients may benefit from adherence counseling even when they claim to be taking their warfarin or the clinician feels they are doing so, particularly several months into their course of therapy.

Low-carbohydrate diets, obesity, and metabolic risk factors for cardiovascular disease.

Given the increased prevalence of obesity in the United States (and its associated cardiovascular risk) despite reduced fat intake, there has been increasing interest in the effect of low-carbohydrate diets on obesity. Recent prospective trials have demonstrated equivalent weight loss on low-carbohydrate versus low-fat diets, but with significantly different effects on metabolic risk factors for cardiovascular disease. Low-carbohydrate diets have more favorable effects on metabolic abnormalities found in insulin resistance syndromes, including serum triglyceride levels, high-density lipoprotein cholesterol levels, and small, dense low-density lipoprotein particles. The translation of these different metabolic effects on cardiovascular disease and events requires future studies. These studies should take into consideration that patients with insulin resistance syndromes would be the most likely group to benefit from carbohydrate restriction.

Novel platelet and vascular roles for immunoreceptor signaling.

The immunoreceptor signaling pathway has classically been defined by its role in mediating intracellular signals downstream of immune receptors on circulating cells, but recent studies have revealed new and unexpected roles for this pathway in vascular biology. In platelets the immunoreceptor signaling pathway is coupled to 2 structurally distinct platelet collagen receptors, glycoprotein VI and integrin alpha2beta1, and is required for the activation of platelets after exposure to vessel wall collagen during plaque rupture. During vascular development immunoreceptor signaling is required for proper formation of the lymphatic system, a role that has revealed the contribution of hematopoietic endothelial progenitors to that process. In conjunction with the identification of new biological roles in vascular cell types, new molecular mechanisms of activating this signaling pathway have been discovered, including activation by integrins and immunoreceptor tyrosine activation motifs (ITAMs) on receptors that do not function as part of the immune response. Here we discuss some of these recent findings and their implications for vascular biology and the treatment of human vascular diseases.

Effects of pioglitazone on lipoproteins, inflammatory markers, and adipokines in nondiabetic patients with metabolic syndrome.

OBJECTIVE: The purpose of this research was to evaluate the short-term effects of pioglitazone (PIO) on high-density lipoprotein cholesterol (HDL-C) and other metabolic parameters in nondiabetic patients with metabolic syndrome (MetSyn). METHODS AND RESULTS: Sixty nondiabetic adults with low HDL-C and MetSyn were randomized to PIO or matching placebo for 12 weeks. PIO increased HDL-C by 15% and 14% at 6 and 12 weeks, respectively, compared with placebo (P<0.001). Changes in HDL-C were correlated to changes in adiponectin (r=0.34; P=0.01) but not to changes in insulin resistance. PIO did not affect serum triglycerides or low-density lipoprotein (LDL) cholesterol concentrations but reduced the number of small LDL particles by 18% (P<0.001). PIO reduced median C-reactive protein levels by 31% (P<0.001) and mean resistin levels by 10% (P=0.02) while increasing mean serum levels of adiponectin by 111% (P<0.001) compared with placebo. PIO did not affect weight and modestly decreased insulin resistance. CONCLUSIONS: In nondiabetic patients with low HDL-C and MetSyn, PIO significantly raised HDL-C and favorably affected lipoprotein particle size, markers of inflammation, and adipokines without changes in triglycerides, LDL-C, or weight. These results suggest that PIO has direct effects on HDL, which may contribute to its antiatherogenic effects.

Effects of rosiglitazone on lipids, adipokines, and inflammatory markers in nondiabetic patients with low high-density lipoprotein cholesterol and metabolic syndrome.

BACKGROUND: PPAR-gamma agonists improve insulin sensitivity and glycemic control in type 2 diabetes and may reduce atherosclerosis progression. Thus, PPAR-gamma agonists may be an effective therapy for metabolic syndrome. However, the full spectrum of potentially antiatherogenic mechanisms of PPAR-gamma agonists have not been fully tested in nondiabetic patients with metabolic syndrome. METHODS AND RESULTS: We performed a prospective, double-blinded, placebo-controlled study of 60 nondiabetic subjects with low high-density lipoprotein cholesterol (HDL-C) level and metabolic syndrome to rosiglitazone 8 mg daily or placebo for 12 weeks. We found no significant effect of rosiglitazone on HDL-C (+5.5% versus +5.8%, P=0.89), and an increase in total cholesterol (+8% versus -1%; P=0.03). Nevertheless, rosiglitazone significantly increased adiponectin (+168% versus +25%; P<0.001), and lowered resistin (-6% versus +4%; P=0.009), C-reactive protein (-32% versus +36%, P=0.002), interleukin (IL)-6 (-22% versus +4%, P<0.001), and soluble tumor-necrosis factor-alpha receptor-2 (-5% versus +7%, P<0.001). CONCLUSIONS: These findings suggest that rosiglitazone, presumably through its PPAR-gamma agonist properties, has direct effects on inflammatory markers and adipokines in the absence of favorable lipid effects. These findings may help explain the mechanism underlying the possible antiatherosclerotic effects of rosiglitazone.

Stress test criteria used in the conservative arm of the FRISC-II trial underdetects surgical coronary artery disease when applied to patients in the VANQWISH trial.

OBJECTIVES: We sought to determine whether the stringent stress test criteria for crossover to cardiac catheterization in the conservative arm of the Fast Revascularization During Instability in Coronary Artery Disease (FRISC-II) trial subjected this strategy to a disadvantage by failing to identify patients with surgical coronary artery disease (CAD). BACKGROUND: In FRISC-II, an invasive strategy provided superior outcomes compared with a conservative strategy for patients with acute coronary syndromes. However, compared with the stress test criteria for crossover to catheterization in the Veterans Affairs Non-Q-Wave Infarction Strategies in Hospital (VANQWISH) trial, the FRISC-II criteria were more restrictive and did not use nuclear imaging or pharmacologic stress testing. METHODS: We analyzed the conservative arm of VANQWISH to identify the prevalence of surgical CAD in those patients who met the VANQWISH, but not FRISC-II, criteria for catheterization. RESULTS: Of 385 VANQWISH patients, 90 (23%) met the FRISC-II criteria for catheterization. Another 98 patients (25%) met only VANQWISH stress test criteria (60 patients by exercise and 38 by pharmacologic nuclear stress testing). Among subjects who underwent predischarge angiography, those meeting only VANQWISH stress test criteria had a high prevalence of surgical CAD (51%), comparable to patients who met FRISC-II criteria (54%, p = 0.805). CONCLUSIONS: The overly stringent risk stratification protocol for conservative-arm patients in FRISC-II could have failed to identify almost as many patients with surgical CAD as it identified. A lower threshold for catheterization in the FRISC-II conservative patients might have improved their outcomes and therefore diminished the putative benefit of an invasive strategy.

Free fatty acids, insulin resistance, and corrected qt intervals in morbid obesity: effect of weight loss during 6 months with differing dietary interventions.

OBJECTIVE: To assess whether shortening of the corrected QT (QTc) interval is most closely associated with changes in weight, insulin resistance, or free fatty acids (FFAs) (or some combination of these factors). METHODS: We randomized 75 severely obese subjects without diabetes to either a low-carbohydrate or a conventional low-fat weight-loss diet for 6 months. We measured QTc, insulin sensitivity, body mass index, and FFAs at baseline and at 6 months. Analysis was performed to determine whether improvement in weight, in insulin resistance, or in FFAs has the greatest effect on reducing the QTc interval. RESULTS: "Completers" of both the low-carbohydrate diet (N = 25) and the low-fat diet (N = 22) had a decrease in weight, but the weight loss was greater in the low-carbohydrate group. A statistically significant decrease in QTc from baseline was observed only in the low-carbohydrate group. QTc in the low-carbohydrate group correlated with improvement in insulin resistance, but this finding was not significant after correction for the greater weight loss. FFAs or weight loss was not correlated with QTc in either dietary group. CONCLUSION: Low-carbohydrate dieting is associated with a greater decrease in the QTc interval in comparison with low-fat dieting. Improvements in insulin resistance seem to have a relatively weak mechanistic role, and a decrease in FFAs has no apparent role in the reduction of the QTc interval.

The effects of low-carbohydrate versus conventional weight loss diets in severely obese adults: one-year follow-up of a randomized trial.

BACKGROUND: A previous paper reported the 6-month comparison of weight loss and metabolic changes in obese adults randomly assigned to either a low-carbohydrate diet or a conventional weight loss diet. OBJECTIVE: To review the 1-year outcomes between these diets. DESIGN: Randomized trial. SETTING: Philadelphia Veterans Affairs Medical Center. PARTICIPANTS: 132 obese adults with a body mass index of 35 kg/m2 or greater; 83% had diabetes or the metabolic syndrome. INTERVENTION: Participants received counseling to either restrict carbohydrate intake to <30 g per day (low-carbohydrate diet) or to restrict caloric intake by 500 calories per day with <30% of calories from fat (conventional diet). MEASUREMENTS: Changes in weight, lipid levels, glycemic control, and insulin sensitivity. RESULTS: By 1 year, mean (+/-SD) weight change for persons on the low-carbohydrate diet was -5.1 +/- 8.7 kg compared with -3.1 +/- 8.4 kg for persons on the conventional diet. Differences between groups were not significant (-1.9 kg [95% CI, -4.9 to 1.0 kg]; P = 0.20). For persons on the low-carbohydrate diet, triglyceride levels decreased more (P = 0.044) and high-density lipoprotein cholesterol levels decreased less (P = 0.025). As seen in the small group of persons with diabetes (n = 54) and after adjustment for covariates, hemoglobin A1c levels improved more for persons on the low-carbohydrate diet. These more favorable metabolic responses to a low-carbohydrate diet remained significant after adjustment for weight loss differences. Changes in other lipids or insulin sensitivity did not differ between groups. LIMITATIONS: These findings are limited by a high dropout rate (34%) and by suboptimal dietary adherence of the enrolled persons. CONCLUSION: Participants on a low-carbohydrate diet had more favorable overall outcomes at 1 year than did those on a conventional diet. Weight loss was similar between groups, but effects on atherogenic dyslipidemia and glycemic control were still more favorable with a low-carbohydrate diet after adjustment for differences in weight loss.

A randomized study comparing the effects of a low-carbohydrate diet and a conventional diet on lipoprotein subfractions and C-reactive protein levels in patients with severe obesity.

PURPOSE: To compare the effects of a low-carbohydrate diet and a conventional (fat- and calorie-restricted) diet on lipoprotein subfractions and inflammation in severely obese subjects. METHODS: We compared changes in lipoprotein subfractions and C-reactive protein levels in 78 severely obese subjects, including 86% with either diabetes or metabolic syndrome, who were randomly assigned to either a low-carbohydrate or conventional diet for 6 months. RESULTS: Subjects on a low-carbohydrate diet experienced a greater decrease in large very low-density lipoprotein (VLDL) levels (difference = -0.26 mg/dL, P = 0.03) but more frequently developed detectable chylomicrons (44% vs. 22%, P = 0.04). Both diet groups experienced similar decreases in the number of low-density lipoprotein (LDL) particles (difference = -30 nmol/L, P = 0.74) and increases in large high-density lipoprotein (HDL) concentrations (difference = 0.70 mg/dL, P = 0.63). Overall, C-reactive protein levels decreased modestly in both diet groups. However, patients with a high-risk baseline level (>3 mg/dL, n = 48) experienced a greater decrease in C-reactive protein levels on a low-carbohydrate diet (adjusted difference = -2.0 mg/dL, P = 0.005), independent of weight loss. CONCLUSION: In this 6-month study involving severely obese subjects, we found an overall favorable effect of a low-carbohydrate diet on lipoprotein subfractions, and on inflammation in high-risk subjects. Both diets had similar effects on LDL and HDL subfractions.

Usefulness of the TIMI risk score in predicting both short- and long-term outcomes in the Veterans Affairs Non-Q-Wave Myocardial Infarction Strategies In-Hospital (VANQWISH) Trial.

We sought to test the validity and clinical utility of the Thrombolysis In Myocardial Infarction (TIMI) risk score for patients who have non-Q-wave myocardial infarction. A post hoc analysis of the Veterans Affairs Non-Q-Wave Infarction Strategies In-Hospital (VANQWISH) Trial was performed, wherein patients were assigned a TIMI risk score from which both 30-day and 12-month outcomes (death, nonfatal myocardial infarction, or urgent revascularization) were assessed. At 30 days, the TIMI risk score showed a close match between observed and predicted probabilities of events after adjustment for overall event rates. The event rate at 30 days was 6% for a score of 0 to 2, 10% for a score of 3, 13% for a score of 4, and 14% for a score of 5 to 7 (p = 0.003 and c statistic 0.59). Discriminative ability of the score was greater in the conservative group at 30 days (p = 0.0004, c statistic 0.67). The score remained modestly predictive of events at 1 year (c statistic 0.60). Conservative strategy patients had better 30-day outcomes than the invasive strategy patients if their score was 0 to 2 (odds ratio 0.24, 95% confidence interval 0.08 to 0.76). No significant difference in outcomes between strategies was detected for a score > or =3. The TIMI risk score provides moderate incremental prognostic information in high-risk patients, during both short- and long-term follow-up.

Modafinil and cocaine: a double-blind, placebo-controlled drug interaction study.

Modafinil is a novel compound that is approved for the treatment of narcolepsy. It is now being studied as a potential treatment for cocaine dependence. Cocaine withdrawal symptoms are associated with poor clinical outcome and are likely to be reversed by modafinil. In addition, the neurotransmitter actions of modafinil are opposite to cocaine-induced neuroadaptations affecting dopamine and glutamate reward circuits. Since cocaine-dependent subjects might use cocaine during a clinical trial with modafinil, this study tested the safety of intravenous cocaine (30 mg) in combination with modafinil. Each of seven subjects received a baseline (open-label) cocaine infusion. Three subsequent cocaine infusions were administered after subjects received 4 days of low dose modafinil (200 mg/day), high dose modafinil (400 mg/day), or placebo in randomized double-blind sequences. One subject received placebo prior to all infusions. Our results indicate that co-administering modafinil and a single dose of intravenous cocaine is not associated with medical risk in terms of blood pressure, pulse, temperature, or electrocardiogram measures. Furthermore, pretreatment with modafinil did not intensify cocaine euphoria or cocaine-induced craving. In fact, cocaine euphoria was significantly blunted (P=0.02) in one of our subjective measures.

Clinical exacerbations as a surrogate end point in heart failure research.

BACKGROUND: We examined the utility of an index of clinical exacerbations of heart failure (HF) as a surrogate measure of outcome for use in modestly sized clinical trials and observational studies. METHODS: Electronic records of 189 outpatients with HF in a US Veterans Affairs Medical Center were examined over a 2- to 3-year period. Data collected included patient characteristics, clinical exacerbations of HF, hospitalizations, and deaths. Subsets of patient were also assessed for HF-related level of functioning. RESULTS: Episodes of clinical exacerbation could be detected reliably (kappa = .83). An index of episodes (number of episodes divided by the time in years) was associated with lower quality of life, higher functional class, increased rate of HF hospitalization, poorer exercise tolerance, and up to 30% increased risk of mortality across 2 years. CONCLUSIONS: The index of HF exacerbations is potentially a useful surrogate end point for use in clinical HF research.

Inhibition of microsomal triglyceride transfer protein alone or with ezetimibe in patients with moderate hypercholesterolemia.

BACKGROUND: Many patients with coronary heart disease do not achieve recommended LDL-cholesterol levels, due to either intolerance or inadequate response to available lipid-lowering therapy. Microsomal triglyceride transfer protein (MTP) inhibitors might provide an alternative way to lower LDL-cholesterol levels. We tested the safety and LDL-cholesterol-lowering efficacy of an MTP inhibitor, AEGR-733 (Aegerion Pharmaceuticals Inc., Bridgewater, NJ), alone and in combination with ezetimibe. METHODS: We performed a multicenter, double-blind, 12-week trial, which included 84 patients with hypercholesterolemia. Patients were randomly assigned ezetimibe 10 mg daily (n = 29); AEGR-733 5.0 mg daily for the first 4 weeks, 7.5 mg daily for the second 4 weeks and 10 mg daily for the last 4 weeks (n = 28); or ezetimibe 10 mg daily and AEGR-733 administered with the dose titration described above (n = 28). RESULTS: Ezetimibe monotherapy led to a 20-22% decrease in LDL-cholesterol concentrations. AEGR-733 monotherapy led to a dose-dependent decrease in LDL-cholesterol concentration: 19% at 5.0 mg, 26% at 7.5 mg and 30% at 10 mg. Combined therapy produced similar but larger dose-dependent decreases (35%, 38% and 46%, respectively). The number of patients who discontinued study drugs owing to adverse events was five with ezetimibe alone, nine with AEGR-733 alone, and four with combined ezetimibe and AEGR-733. Discontinuations from AEGR-733 were due primarily to mild transaminase elevations. CONCLUSIONS: Inhibition of LDL production with low-dose AEGR-733, either alone or in combination with ezetimibe, could be an effective therapeutic option for patients unable to reach target LDL-cholesterol levels.

Social support and self-care of patients with heart failure.

BACKGROUND: Social support can influence treatment adherence of patients with chronic illnesses, which may explain the positive effects of social support on heart failure (HF) outcomes. PURPOSE: To investigate the effects of social support among patients with HF, we examined whether aspects of social support were associated with self-care, including medication adherence, dietary adherence, and HF symptom monitoring functions. METHODS: We recruited 74 patients with HF from cardiology clinics of a Veterans Affairs Medical Center and a university-affiliated hospital, and tested the relationships between social support and the patients' self-care. RESULTS: Consistent with previous research in older adults, family members, especially spouses, were often involved in the medical care of patients with chronic HF and provided a range of levels of support to patients. Self-care was generally poor, as measured across several self-care domains. Perceived social support was moderately associated with relatively better self-reported medication and dietary adherence, and other aspects of self-care such as daily weighing. CONCLUSIONS: These findings suggest that a relatively higher level of self-care is an important correlate of social support and may explain how social support influences HF outcomes. This study also suggests that family members should play a greater part in clinical care focused on improving self-care.

Dyslipidemia in type 2 diabetes mellitus.

Cardiovascular disease is a significant cause of morbidity and mortality in patients with diabetes mellitus (DM). DM is now recognized as a risk equivalent for coronary heart disease. The lipid profile in patients with type 2 DM is characterized by elevated triglycerides, low levels of high-density lipoprotein cholesterol, and small dense low-density lipoprotein cholesterol (LDLC) particles and is believed to be a key factor promoting atherosclerosis in these patients. Both primary and secondary prevention studies have provided ample evidence that aggressive statin therapy reduces cardiovascular end points in patients with DM. In all persons with DM, current treatment guidelines recommend reduction of LDLC to less than 100 mg/dL, regardless of baseline lipid levels. Lowering LDLC to less than 70 mg/dL may provide even greater benefits, particularly in very high risk patients with DM and coronary heart disease.