A quantitative measure of diabetes risk in community practice impacts clinical decisions: the PREVAIL initiative.

BACKGROUND AND AIMS: While predictive tools are being developed to identify those at highest risk for developing diabetes, little is known whether these assays affect clinical care. METHODS AND RESULTS: Thirty sites who used the PreDx(®) (Tethys BioScience, Emeryville, CA) abstracted clinical information from baseline clinic visits prior to a PreDx test and from the most recent visit at time of abstraction. All visits occurred between May 2008-April 2011 (median follow-up 198 days, IQR 124-334). The primary analysis was the influence of the PreDx test (5-year diabetes prediction) on subsequent care; descriptive statistics were used to summarize baseline and follow-up variables. Overall 913 patients with 2 abstracted visits were included. Relative to baseline, median SBP decreased 1.5 mmHg (p = 0.039), DBP decreased 2 mmHg (p < 0.001), LDL-C decreased 4 mg/dL (p = 0.009), and HDL-C increased 2 mg/dL (p < 0.001) at follow-up. Behavioral or lifestyle counseling was not significantly different from baseline to follow-up (71.2% vs. 68.1% (p = 0.077), but BMI was lower by 0.2 kg/m(2) at follow up (p = 0.013). At follow-up, more patients were prescribed metformin (13.7% vs. 9.7%, p < 0.001). A higher PreDx score was significantly associated with metformin prescription (p = 0.0003), lifestyle counseling (p = 0.0099), and a lower BMI at follow-up (p = 0.007). CONCLUSION: The use of a prognostic test in patients perceived to be high risk for diabetes was associated with a modest but significant increase in the prescription of metformin and lifestyle interventions and a reduction in BMI.

Modulation of the renin-angiotensin-aldosterone system for the secondary prevention of stroke.

Recurrent stroke is a major public health concern and new treatment strategies are needed. While modulation of the renin angiotensin aldosterone system (RAAS) has proven effective in reducing recurrent cardiac events, its role in preventing recurrent cerebrovascular events remains unclear. RAAS is both a circulating and tissue based hormonal system that regulates homeostasis and tissue responses to injury in both the CNS and the periphery, via the activity of angiotensin II (Ang II). Vascular and hematologic effects induced by Ang II including endothelial dysfunction, vascular structural changes, inflammation, hemostasis, and fibrinolysis are increasingly linked to the occurrence of cerebrovascular events. Animal models have shown that RAAS modulation may be protective in cerebrovascular disease. The HOPE and LIFE trials support the role of blood pressure independent mechanisms of RAAS modulation for improving outcomes in a broad range of patients with cardiovascular disease but do not specifically address recurrent stroke prevention. PROGRESS, a trial of secondary stroke prevention, demonstrates that blood pressure reduction with a combination strategy including the routine use of ACE inhibitors prevents recurrent stroke. Current evidence suggests that the RAAS plays an important role in the development and progression of cerebrovascular disease. Modulation of the RAAS holds promise for the secondary prevention of stroke, however, ongoing clinical trials will better define the exact role of ACE inhibitor and angiotensin II Type 1 receptor blocker therapy in stroke survivors.

Effectiveness of statins in acute coronary syndromes.

Over the past several years, results of clinical trials of lipid lowering have increased our understanding of the pathophysiology of coronary atherosclerosis and ischemia. Evidence is accumulating that cholesterol lowering has potential anti-ischemic effects and may have immediate consequences that have a favorable impact on coronary events, possibly even acute coronary syndromes. Yet, less than one half of all patients hospitalized for acute coronary syndromes have their cardiovascular risks appropriately modified. The results of recent statin trials provide impetus for the implementation of aggressive risk-reduction strategies in patients with coronary atherosclerosis, including those with recent acute coronary syndromes. Prevention is now a viable therapeutic goal.

A propensity analysis of cigarette smoking and mortality with consideration of the effects of alcohol.

Although it is well established that cigarette smoking causes excess mortality, the extent of the increased risk has been challenged because self-selection biases and confounding factors may not have been adequately accounted for in prior studies. We therefore performed a propensity analysis on a population-based cohort. A logistic regression model was used to generate a propensity score for current smoking in 6,099 adults (mean age 46 years, 54% men, 36% current smokers) participating in the National Heart Lung and Blood Institute's (NHLBI) Lipid Research Clinic Prevalence Study. During 12 years of follow-up, 513 subjects (8%) died. After adjusting for age, current smoking was strongly associated with death (compared with never and former smokers, relative risk [RR] 2.69, 95% confidence interval [CI] 1.98 to 0.64, p <0.0001 and RR 1.79, 95% CI 1.26 to 2.55, p = 0.001, respectively). After adjusting for a propensity score based on 27 covariates and the covariates themselves, current smoking remained strongly and independently predictive of excessive death risk in smokers compared with never and former smokers (adjusted RR 2.96, 95% CI 2.16 to 4.05, p <0.0001 and adjusted RR 1.87, 95% CI 1.31 to 2.67, p = 0.0006, respectively). Although smokers were more likely to also drink alcohol, an interaction was noted, whereby, after adjustment for propensity score and other covariates, current smoking was associated with a moderately strong increase in mortality among drinkers (adjusted RR 2.00, 95% CI 1.42 to 2.82, p <0.0001), but was also associated with a markedly increased death risk among nondrinkers (adjusted RR 4.74, 95% CI 3.24 to 6.92, p <0.0001). The independent association of smoking with death even after a rigorous propensity analysis argues that it is highly unlikely that the link between smoking and mortality is materially biased or confounded.

HDL cholesterol level predicts survival in men after coronary artery bypass graft surgery: 20-year experience from The Cleveland Clinic Foundation.

BACKGROUND: HDL cholesterol (HDL-C) is an important independent predictor of atherosclerosis, yet the role that HDL-C may play in the prediction of long-term survival after CABG remains unclear. The risk associated with a low HDL-C level in post-CABG men has not been delineated in relation to traditional surgical variables such as the use of arterial conduits, left ventricular function, and extent of disease. METHODS AND RESULTS: We performed a prospective, observational study of 432 men who underwent CABG between 1978 and 1979 in whom preoperative HDL-C values were available. Baseline lipid and lipoprotein values, history of diabetes mellitus and hypertension, left ventricular ejection fraction, extent of disease, and use of internal thoracic arteries were recorded. Hazard ratios (HRs) were determined in the patients with and without a low HDL-C level, which was defined as the lowest HDL-C quartile (HDL-C 35 mg/dL) were 50% more likely to survive at 15 years than were patients with low HDL-C level (35 mg/dL were 50% more likely to survive without a subsequent myocardial infarction or revascularization (HR 1.42, P:=0.02). CONCLUSIONS: HDL-C is an important predictor of survival in post-CABG patients. In this study of >8500 patient-years of follow-up, HDL-C was the most important metabolic predictor of post-CABG survival. One third fewer patients survive at 15 years if their HDL-C levels are

Clinical benefit of glycoprotein IIb/IIIa blockade with Abciximab is independent of gender: pooled analysis from EPIC, EPILOG and EPISTENT trials. Evaluation of 7E3 for the Prevention of Ischemic Complications. Evaluation in Percutaneous Transluminal Coronary Angioplasty to Improve Long-Term Outcome with Abciximab GP IIb/IIIa blockade. Evaluation of Platelet IIb/IIIa Inhibitor for Stent.

OBJECTIVES: We sought to determine the efficacy and safety of platelet glycoprotein IIb/IIIa receptor (GP IIb/IIIa) blockade with abciximab in women undergoing percutaneous coronary intervention. BACKGROUND: Although gender differences in response to platelet glycoprotein IIb/IIIa receptor blockade have been described, there have been no large clinical studies to assess these differences. METHODS: Outcomes were determined using meta-analysis technique. RESULTS: In the pooled analysis, the primary end point of death, myocardial infarction (MI) or urgent revascularization within 30 days was reduced from 11.3% to 5.8% (p<0.001) in men and from 12.7% to 6.5% (p<0.001) in women treated with abciximab. At six months, death, MI or urgent revascularization was reduced from 14.1% to 8.3% (p<0.001) in men and 16.0% to 9.9% (p<0.001) in women receiving abciximab. At one year, mortality was reduced from 2.7% to 1.9% (p = 0.06) in men and 4.0% to 2.5% (p = 0.03) in women treated with abciximab. Major bleeding events occurred in 2.9% versus 3.0% (p = 0.96) of women and 2.7% versus 1.3% (p = 0.003) of men treated with placebo versus abciximab, respectively. Minor bleeding events occurred in 4.7% versus 6.7% (p = 0.01) of women and 2.3% versus 2.2% (p = 0.94) of men treated with placebo versus abciximab, respectively. CONCLUSIONS: This pooled analysis demonstrated no gender difference in protection from major adverse outcomes with GP IIb/IIIa inhibition with abciximab. Although women had higher rates of both major and minor bleeding events with abciximab compared with men, major bleeding in women was similar with and without abciximab. There was a small increased risk of minor bleeding with abciximab in women.

Cardiac rehabilitation participation patterns in a large, tertiary care center: evidence for selection bias.

BACKGROUND: Clinical practice guidelines have been published for cardiac rehabilitation, directing programs to address secondary risk-reduction issues. The role of risk factor profiles in the referral of patients to cardiac rehabilitation programs has not been evaluated. METHODS: Patients from the Cardiovascular Information Registry at the Cleveland Clinic Foundation (CCF) who entered the CCF hospital-based cardiac rehabilitation program (n = 371) were compared with those who did not participate in the CCF program (n = 2960) with respect to gender, demographics, and risk factor profile for CAD. A random subset of those who did not participate in the CCF program (n = 100) was interviewed by phone to determine participation patterns in other rehabilitation programs. RESULTS: Only 11% of patients participated in CCF-based program. Standard risk factors were similar between participants and nonparticipants. Rehabilitation patients were younger (63 +/- 10 versus 66 +/- 10, P < 0.01) and as a group had better left ventricular function (moderate-severe left ventricle: 16% versus 23%, P < 0.01) than nonparticipants. Women were underrepresented in the CCF rehabilitation population (20% versus 30%, P < 0.01). Of the phone survey sample, 21% of patients entered other community-based rehabilitation programs. Similar trends with respect to risk factors, younger age, and better left ventricular function were noted for the community subset. However, women accounted for a greater percentage of the participants in the community programs than the CCF-based program (42.8% versus 19.7%, P < 0.03). CONCLUSIONS: Conclusions based on institution-specific programs likely underestimate overall participation in cardiac rehabilitation. Traditional risk factors apparently are not considered when referring patients to cardiac rehabilitation programs. Younger patients with lower mortality risks preferentially participate in rehabilitation programs. Women are more likely to participate in community-based programs. Overall use of cardiac rehabilitation programs remains low.

Heart rate recovery after submaximal exercise testing as a predictor of mortality in a cardiovascularly healthy cohort.

BACKGROUND: Abnormal heart rate recovery after symptom-limited exercise predicts death. It is unknown whether this is also true among patients undergoing submaximal testing. OBJECTIVE: To test the prognostic implications of heart rate recovery in cardiovascularly healthy adults undergoing submaximal exercise testing. DESIGN: Population-based cohort study. SETTING: 10 primary care sites. PARTICIPANTS: 5234 adults without evidence of cardiovascular disease who were enrolled in the Lipid Research Clinics Prevalence Study. MEASUREMENTS: Heart rate recovery was defined as the change from peak heart rate to that measured 2 minutes later (heart rate recovery was defined as < or =42 beats/min). RESULTS: During 12 years of follow-up, 312 participants died. Abnormal heart rate recovery predicted death (relative risk, 2.58 [CI, 2.06 to 3.20]). After adjustment for standard risk factors, fitness, and resting and exercise heart rates, abnormal heart rate recovery remained predictive (adjusted relative risk, 1.55 [CI, 1.22 to 1.98]) (P<0.001). CONCLUSION: Even after submaximal exercise, abnormal heart rate recovery predicts death.

Homocysteine and lipoprotein(a) interact to increase CAD risk in young men and women.

A biochemical link between homocysteine (tHcy) and lipoprotein(a) [Lp(a)] related to fibrin binding has been proposed. This hypothesis has not been specifically examined in human subjects. We sought to determine in a clinical setting whether these risk factors would interact to increase coronary artery disease (CAD) risk. We performed a cross-sectional analysis of 750 men and 403 women referred to a preventive cardiology clinic at the Cleveland Clinic Foundation, in whom baseline tHcy and Lp(a) data were available. Logistic regression after adjusting for standard cardiovascular risk factors was used to estimate the relative risk of CAD in patients with an Lp(a) >/=30 mg/dL and a tHcy >/=17 micromol/L. Neither isolated high tHcy (odds ratio [OR]=1.06, P=0.89) nor isolated high Lp(a) (OR=1.15, P=0.60) appeared to be associated with CAD in women. However, strong evidence of an association was seen when both risk factors were present (OR=4.83, P=0.003). Moreover, this increased risk showed evidence of an interactive effect beyond that attributable to either additive or multiplicative effects of tHcy and Lp(a) (P=0.03). In contrast, both elevated tHcy (OR=1.93, P=0. 05) and elevated Lp(a) (OR=1.87, P=0.01) showed evidence of being independent risk factors for CAD in men. The presence of both risk factors in men did not appear to confer additional risk (OR=2.00, P=0.09), even though ORs as high as 12.4 were observed within specific age intervals. Consistent with prior studies, tHcy and Lp(a) are risk factors, either independently or in concert, for CAD in this clinical population. More significantly, we found evidence that when both risk factors were present in women, the associated risk was greater than what would be expected if the 2 risks were simply acting independently. The absence of such an interactive effect in men may be due to the confounding effects of age manifested as "survivor bias." These clinical findings provide insights into the potential roles of both tHcy and Lp(a) in the pathogenesis of atherosclerosis.

Lipoprotein(a) associated with coronary artery disease in older women: age and gender analysis.

BACKGROUND: Lipoprotein (a) has been associated with increased coronary artery disease (CAD) risk in men, but relatively little data exists in women. While age influences the cardiovascular risk associated with Lp(a) in men, little is known about this phenomenon in women. The impact of gender on Lp(a) has not been fully studied in an ongoing clinical practice. METHODS AND RESULTS: Baseline Lp(a) values were measured in 918 CAD and 829 non-CAD patients (603 females, 1144 males) entering an outpatient prevention clinic. The age-specific association of elevated Lp(a) (> 30 mg/dl) with CAD was examined after adjustment for traditional risk factors. Lp(a) was a significant risk factor (OR = 1.9, CI, 1.4-2.6) in men and women (OR = 1.9, CI 1.3-2.9). In men age < or = 55 years the odds ratio for increased cardiovascular risk in high vs low Lp(a) was 2.5 (CI 1.6-3.9). In men < or = 55, CAD increased from 32 to 61% as Lp(a) progressively rose from < or = 5 to > or = 45 mg/dl (P value for trend < 0.001). No significant increase was observed in men > 55 years (OR = 1.3, CI 0.9-2.1). In women < or = 55 years, the risk of CAD increased from 22 to 35% (OR 1.6, CI 0.8-3.2), and increased from 38 to 63% in women > 55 (OR 2.1, CI 1.3-3.5). Further, of high-risk patients (men < or = 55 and women > 55 years) with an Lp(a) in the range of 20-44 mg/dl (third quartile), younger men showed a greater incidence of CAD (51%) than older women (43%). Both genders revealed substantial risk when the Lp(a) values were above 45 mg/dl. (OR = 3.7, CI = 2.0-6.8 in younger men; OR = 3.3, CI = 1.6-6.6 in older women). CONCLUSIONS: In this cross sectional study of both men and women, elevated Lp(a) was associated with a significantly increased risk of CAD in men and women. While we corroborate previous reports on the lack of association in older men, the determination of an enhanced Lp(a)-related risk in older women was new and unanticipated. Further, in this population of high risk patients, substantial cardiovascular risk appeared to be represented by higher concentrations of Lp(a) in women than observed in men.

Incidence and clinical course of thrombotic thrombocytopenic purpura due to ticlopidine following coronary stenting. EPISTENT Investigators. Evaluation of Platelet IIb/IIIa Inhibitor for Stenting.

CONTEXT: Thrombotic thrombocytopenic purpura (TTP) is a rare and often fatal disorder characterized by thrombocytopenia, microangiopathic hemolytic anemia, mental status changes, and renal dysfunction. Ticlopidine hydrochloride is 1 of several drugs that have been associated with this disorder and is currently used routinely in the approximately 500000 patients per year in the United States who undergo a percutaneous coronary intervention involving a stent. OBJECTIVES: To determine the incidence and describe the clinical course of TTP due to ticlopidine therapy following stenting. DESIGN: Retrospective analysis of cohort of all patients undergoing coronary stenting at the Evaluation of Platelet IIb/IIIa Inhibitor for Stenting (EPISTENT) study sites. SETTING: Sixty-three centers throughout the United States and Canada. PATIENTS: A total of 43322 patients who underwent a percutaneous coronary intervention and received a coronary stent during a 1-year period from 1996 to 1997. MAIN OUTCOME MEASURES: Cases of TTP following stenting during the 1-year period to determine the incidence of TTP due to ticlopidine therapy following coronary stenting. Additional cases were collected from these and other centers across North America to further describe the clinical presentation and course of TTP due to ticlopidine therapy following stenting. RESULTS: Nine cases of TTP following stenting were recognized at the 63 centers during the specified period, giving an incidence of 1 case per 4814 patients treated (0.02%; 95% confidence interval, 1 case per 2533 to 1 case per 10 541 patients treated). Ten additional cases of TTP related to ticlopidine therapy following stenting were identified from other centers, were identified from the primary centers outside the pre-defined period, or involved a noncoronary stent. Four patients (21%) received ticlopidine for 2 weeks or fewer, 14 patients (74%) for 2 to 4 weeks, and 1 patient (5%) for 8 weeks. The mean time of ticlopidine treatment prior to TTP diagnosis was 22 days (range, 5-60 days). The overall mortality rate was 21% (4/19), with all 4 deaths occurring in patients not treated with plasmapheresis, whereas there were no deaths among the 13 patients who received plasmapheresis. CONCLUSION: The findings of a TTP incidence of 0.02% in our cohort of ticlopidine-treated patients following coronary stenting suggests that TTP occurs much more commonly in this population than the estimated incidence of 0.0004% in the general population. The mortality rate for this rare complication exceeds 20%. Limiting ticlopidine therapy to 2 weeks after stenting does not prevent the development of TTP. Rapid diagnosis and treatment that includes plasmapheresis are critical for improved survival.