Aspirin resistance and adverse clinical events in patients with coronary artery disease

Purpose

We sought to determine the clinical significance of aspirin resistance measured by a point-of-care assay in stable patients with coronary artery disease (CAD).

Methods

We used the VerifyNow Aspirin (Accumetrics Inc, San Diego, Calif) to determine aspirin responsiveness of 468 stable CAD patients on aspirin 80 to 325 mg daily for ≥4 weeks. Aspirin resistance was defined as an Aspirin Reaction Unit ≥550. The primary outcome was the composite of cardiovascular death, myocardial infarction (MI), unstable angina requiring hospitalization, stroke, and transient ischemic attack.

Results

Aspirin resistance was noted in 128 (27.4%) patients. After a mean follow-up of 379 ± 200 days, patients with aspirin resistance were at increased risk of the composite outcome compared to patients who were aspirin-sensitive (15.6% vs 5.3%, hazard ratio [HR] 3.12, 95% confidence intervals [CI], 1.65-5.91, P < .001). Cox proportional hazard regression modeling identified aspirin resistance, diabetes, prior MI, and a low hemoglobin to be independently associated with major adverse long-term outcomes (HR for aspirin resistance 2.46, 95% CI, 1.27-4.76, P = .007).

Conclusions

Aspirin resistance, defined by an aggregation-based rapid platelet function assay, is associated with an increased risk of adverse clinical outcomes in stable patients with CAD.     

Antecedent hypertension and the effect of captopril on the risk of adverse cardiovascular outcomes after acute myocardial infarction with left ventricular systolic dysfunction: Insights from the Survival and Ventricular Enlargement Trial

Background

Hypertension is a well-established risk factor for myocardial infarction (MI), but its prognostic importance in survivors of an acute MI is less clear.

Methods

We used Cox proportional hazards models to examine the risk of any major cardiovascular event (cardiovascular death, heart failure, recurrent MI, or stroke)—combined or individual components—and all-cause death and evaluate the efficacy of captopril in 906 patients with hypertension and 1325 patients without hypertension in the Survival and Ventricular Enlargement (SAVE) clinical trial. All patients had survived an acute MI with resultant left ventricular (LV) systolic dysfunction, but without overt heart failure, and were randomized within 3 to 16 days after the index MI to receive either captopril or placebo. The mean (± SD) follow-up period was 42 ± 10 months.

Results

After adjustment for known risk factors, medication use at enrollment, and baseline systolic blood pressure, patients with hypertension had a significant increase in the risk of experiencing a combined cardiovascular event (47.7% vs 31.3%; hazard ratio [HR], 1.49; 95% CI, 1.28-1.74), cardiovascular death (23.4% vs 15.9%; HR, 1.40; 95% CI, 1.12-1.74), heart failure (27.7% vs 15.5%; HR, 1.64; 95% CI, 1.34-2.02), and all-cause death (27.4 vs 19.3%; HR, 1.25; 95% CI, 1.02-1.53), and a similar but statistically non-significant increase in the risk of non-fatal or fatal recurrent MI (17.4% vs 10.9%; HR, 1.27; 95% CI, 0.98-1.65), and non-fatal or fatal stroke (5.0% vs 3.6%; HR, 1.31; 95% CI, 0.81-2.09). Captopril resulted in similar benefits for both patients with and patients without hypertension. The number of combined cardiovascular events prevented for every 100 patients treated with captopril was 7.0 (95% CI, 0.5-13.5) in patients with hypertension and 7.5 (95% CI, 2.6-12.5) in patients without hypertension.

Conclusions

In survivors of an acute MI with LV systolic dysfunction, antecedent hypertension was associated with a greater risk of subsequent adverse cardiovascular events, not directly explained by elevated blood pressure levels. Captopril use was beneficial in both patients with and patients without hypertenson.     

Long-Acting Calcium Antagonists in Patients with Coronary Artery Disease: A Meta-Analysis

Background

The use of calcium channel blockers (CCBs) in patients with coronary artery disease remains controversial, with reports of increased risk of myocardial infarction and all-cause mortality. Short-acting CCBs have an unfavorable hemodynamic profile. The role of long-acting CCBs in patients with coronary artery disease is unknown.

Methods

MEDLINE/CENTRAL/EMBASE database were searched from 1966 to August 2008 for randomized controlled trials of long-acting CCBs in patients with coronary artery disease with follow-up for at least 1 year. We extracted from the studies the baseline characteristics and 6 outcomes: all-cause mortality, cardiovascular mortality, nonfatal myocardial infarction, stroke, angina pectoris, and heart failure.

Results

Of the 100 randomized controlled trials of CCBs in patients with coronary artery disease, 15 studies evaluating 47,694 patients fulfilled our inclusion criteria. When compared with the comparison group (including placebo), CCBs were not associated with an increased risk of all-cause mortality (relative risk [RR] 0.99; 95% confidence interval [CI], 0.94-1.05), cardiovascular mortality (RR 1.03; 95% CI, 0.95-1.11), nonfatal myocardial infarction (RR 0.96; 95% CI, 0.87-1.06), or heart failure (RR 0.86; 95% CI, 0.71-1.05), and with a 21% reduction in the risk of stroke (95% CI, 0.70-0.89) and 18% reduction in the risk of angina pectoris (95% CI, 0.72-0.94). When compared with placebo, CCBs resulted in a 28% reduction in the risk of heart failure (95% CI, 0.73-0.92). The results were similar for both dihydropyridines and nondihydropyridine CCBs.

Conclusions

In patients with coronary artery disease, long-acting CCBs (either dihydropyridines or nondihydropyridines), were associated with a reduction in the risk of stroke, angina pectoris, and heart failure, with similar outcomes for other cardiovascular events as the comparison group.     

Glyburide increases risk in patients with diabetes mellitus after emergent percutaneous intervention for myocardial infarction — A nationwide study

Background

Sulfonylureas have been linked to an increased cardiovascular risk by inhibition of myocardial preconditioning. Whether individual sulfonylureas affect outcomes in diabetic patients after emergent percutaneous coronary intervention for myocardial infarction is unknown.

Methods

All Danish patients receiving glucose-lowering drugs admitted with myocardial infarction between 1997 and 2006 who underwent emergent percutaneous coronary intervention were identified from national registers. Multivariable Cox proportional hazards models were used to analyze the risk of cardiovascular mortality and morbidity associated with sulfonylureas.

Results

A total of 926 patients were included and 163 (17.6%) patients died during the first year of which 155 (16.7%) were cardiovascular deaths. The most common treatment was sulfonylureas which were received by 271 (29.3%) patients, and 129 (13.9%) received metformin. Cox proportional hazard regression analyses adjusted for age, sex, calendar year, comorbidity and concomitant pharmacotherapy showed an increased risk of cardiovascular mortality (hazard ratio [HR] 2.91, 95% confidence interval [CI] 1.26-6.72 ; p = 0.012), cardiovascular mortality and nonfatal myocardial infarction (HR 2.69 , 95% CI 1.21-6.00; p = 0.016), and all-cause mortality (HR 2.46, 95% CI 1.11-5.47; p = 0.027), respectively, with glyburide compared to metformin.

Conclusions

Glyburide is associated with increased cardiovascular mortality and morbidity in patients with diabetes mellitus undergoing emergent percutaneous coronary intervention after myocardial infarction. Early reperfusion therapy is the mainstay in modern treatment of myocardial infarction and the time may have come to discard glyburide in favour of sulfonylureas that do not appear to confer increased cardiovascular risk.     

Adopting moderate alcohol consumption in middle age: subsequent cardiovascular events

Purpose

Moderate alcohol use is part of a healthy lifestyle, yet current guidelines caution nondrinkers against starting to drink alcohol in middle age. The purpose of this study was to evaluate whether adopting moderate alcohol consumption in middle age would result in subsequent lower cardiovascular risk.

Methods

This study examined a cohort of adults aged 45-64 years participating in the Atherosclerosis Risk in Communities study over a 10-year period. The primary outcome was fatal or nonfatal cardiovascular events.

Results

Of 7697 participants who had no history of cardiovascular disease and were nondrinkers at baseline, within a 6-year follow-up period, 6.0% began moderate alcohol consumption (2 drinks per day or fewer for men, 1 drink per day or fewer for women) and 0.4% began heavier drinking. After 4 years of follow-up, new moderate drinkers had a 38% lower chance of developing cardiovascular disease than did their persistently nondrinking counterparts. This difference persisted after adjustment for demographic and cardiovascular risk factors (odds ratio 0.62, 95% confidence interval, 0.40-0.95). There was no difference in all-cause mortality between the new drinkers and persistent nondrinkers (odds ratio 0.71, 95% confidence interval, 0.31-1.64).

Conclusion

People who newly begin consuming alcohol in middle age rarely do so beyond recommended amounts. Those who begin drinking moderately experience a relatively prompt benefit of lower rates of cardiovascular disease morbidity with no change in mortality rates after 4 years.     

Improving risk assessment with cardiac testing in peripheral arterial disease

Purpose

The study’s objective was to evaluate the prognostic value of left ventricular ejection fraction and stress-induced ischemia during dobutamine stress echocardiography, in addition to ankle-brachial index measurements and clinical risk factors in patients with suspected or known peripheral arterial disease.

Methods

In 852 patients with suspected or known peripheral arterial disease (mean age 63 years, 70% male), the ankle-brachial index was measured, left ventricular ejection fraction was assessed, and all patients underwent additional stress testing. Endpoints were all-cause mortality and hard cardiac events (cardiac death or nonfatal myocardial infarction).

Results

During a mean follow-up of 7.6 ± 4.4 years, death occurred in 288 patients (34%), and hard cardiac events occurred in 216 patients (25%). Mean left ventricular ejection fraction was 50% ± 17%, and stress-induced ischemia was observed in 352 patients (41%). In multivariate analysis with adjustment for clinical risk factors and ankle-brachial index, each 5% decrease in left ventricular ejection fraction was associated with increased all-cause mortality (hazard ratio [HR] 1.05, 95% confidence interval [CI], 1.02-1.09) and hard events (HR 1.14, 95% CI, 1.08-1.21). Stress-induced ischemia also independently predicted all-cause mortality (HR 2.01, 95% CI, 1.38-2.79) and hard events (HR 2.06, 95% CI, 1.39-3.08). Left ventricular ejection fraction and stress-induced ischemia provided incremental prognostic information over clinical data and ankle-brachial index values (P <.001).

Conclusions

Left ventricular ejection fraction and stress-induced ischemia independently predict long-term outcome and improve prognostic risk assessment, in addition to ankle-brachial index and clinical risk factors in patients with suspected or known peripheral arterial disease.     

Impact of comprehensive and intensive treatment of risk factors concerning cardiovascular mortality in secondary prevention: MIRVAS Study

Introduction and objectives

The aim was to determine whether secondary prevention involving the comprehensive and intensive treatment of cardiovascular risk factors reduces cardiovascular events and cardiovascular mortality at 3-year follow up.

Methods

The study design comprised a randomized, controlled, open trial in a routine clinical practice setting. In total, 247 patients who presented with acute coronary syndrome or stroke were selected. They were randomized to comprehensive and intensive treatment of cardiovascular risk factors (n=121) or to follow-up based on usual care (n=126). The main study outcomes were the number of cardiovascular events and cardiovascular mortality at 3-year follow-up. The percentage of patients in whom each risk factor was successfully controlled was a secondary outcome.

Results

Overall, 88.8% of patients assigned to the intensive treatment group had a low-density lipoprotein cholesterol level <100 mg/dl compared with 56.4% of the usual-care group (relative risk [RR]=1.57; 95% confidence interval [CI], 1.28-1.93), and 75.7% of diabetics had a hemoglobin A_1c <7% compared with 28.6% of the usual-care group (RR=2.65; 95% CI, 1.13-6.19). There were four deaths due to cardiovascular causes and 26 nonfatal events in the intensive treatment group versus 17 deaths and 54 nonfatal events in the usual-care group. The cumulative survival rate at 3 years was 97.4% in the intervention group and 85.5% in the control group (p=.003).

Conclusions

Secondary prevention involving comprehensive and intensive treatment of cardiovascular risk factors reduced both morbidity and mortality at 3-year follow up.Full English text available from: www.revespcardiol.org     

Biomarkers to predict recurrent cardiovascular disease: the Heart and Soul Study

Purpose

The study purpose was to evaluate the ability of 6 biomarkers to improve the prediction of cardiovascular events among persons with established coronary artery disease.

Background

Cardiovascular risk algorithms are designed to predict the initial onset of coronary artery disease but are less effective in persons with preexisting coronary artery disease.

Methods

We examined the association of N-terminal prohormone brain natriuretic peptide (Nt-proBNP), cystatin C, albuminuria, C-reactive protein (CRP), interleukin-6, and fibrinogen with cardiovascular events in 979 Heart and Soul Study participants with coronary artery disease after adjusting for demographic, lifestyle, and behavior variables; cardiovascular risk factors; cardiovascular disease severity; medication use; and left ventricular ejection fraction. The outcome was a composite of stroke, myocardial infarction, and coronary heart disease death during an average of 3.5 years of follow-up.

Results

During follow-up, 142 participants (15%) developed cardiovascular events. The highest quartiles (vs lower 3 quartiles) of 5 biomarkers were individually associated with cardiovascular risk after multivariate analysis: Nt-proBNP hazard ratio (HR) = 2.13 (95% confidence interval [CI], 1.43-3.18); cystatin C HR = 1.72 (95% CI, 1.10-2.70); albuminuria HR = 1.71 (95% CI, 1.15-2.54); CRP HR = 2.00 (95% CI, 1.40-2.85); and interleukin-6 HR = 1.76 (95% CI, 1.22-2.53). When all biomarkers were included in the multivariable analysis, only Nt-proBNP, albuminuria, and CRP remained significant predictors of events: HR = 1.88 (95% CI, 1.23-2.85), HR = 1.63 (95% CI, 1.09-2.43), and HR = 1.82 (95% CI, 1.24-2.67), respectively. The area under the receiver operator curve for clinical predictors alone was 0.73 (95% CI, 0.68-0.78); adding Nt-proBNP, albuminuria, and CRP significantly increased the area under the receiver operator curve to 0.77 (95% CI, 0.73-0.82, P <.005).

Conclusion

Among persons with prevalent coronary artery disease, biomarkers reflecting hemodynamic stress, kidney damage, and inflammation added significant risk discrimination for cardiovascular events.     

Effect of aspirin on mortality in the primary prevention of cardiovascular disease

Objective

The lack of a mortality benefit of aspirin in prior meta-analyses of primary prevention trials of cardiovascular disease has contributed to uncertainty about the balance of benefits and risks of aspirin in primary prevention. We performed an updated meta-analysis of randomized controlled trials of aspirin to obtain best estimates of the effect of aspirin on mortality in primary prevention.

Methods

Eligible articles were identified by searches of electronic databases and reference lists. Outcomes of interest were all-cause mortality, cardiovascular mortality, myocardial infarction, stroke, and bleeding. Data were pooled from individual trials using the DerSimonian-Laird random-effects model, and results are presented as relative risk (RR) and 95% confidence intervals (CIs).

Results

Nine randomized controlled trials enrolling 100,076 participants were included. Aspirin reduced all-cause mortality (RR 0.94; 95% CI, 0.88-1.00), myocardial infarction (RR 0.83; 95% CI, 0.69-1.00), ischemic stroke (RR 0.86; 95% CI, 0.75-0.98), and the composite of myocardial infarction, stroke, or cardiovascular death (RR 0.88; 95% CI, 0.83-0.94), but did not reduce cardiovascular mortality (RR 0.96; 95% CI, 0.84-1.09). Aspirin increased the risk of hemorrhagic stroke (RR 1.36; 95% CI, 1.01-1.82), major bleeding (RR 1.66; 95% CI, 1.41-1.95), and gastrointestinal bleeding (RR 1.37; 95% CI, 1.15-1.62). A lack of availability of patient-level data precluded exploration of benefits and risks of aspirin in key subgroups.

Conclusion

Aspirin prevents deaths, myocardial infarction, and ischemic stroke, and increases hemorrhagic stroke and major bleeding when used in the primary prevention of cardiovascular disease.     

Preoperative Cardiac Risk Index Predicts Long-term Mortality and Health Status

Objectives

Peripheral arterial disease patients undergoing vascular surgery are known to be at risk for the occurrence of (late) cardiovascular events. Before surgery, the perioperative cardiac risk is commonly assessed using the Lee Risk Index score, a combination of 6 cardiac risk factors. This study assessed the predictive value of the Lee Risk Index for late mortality and long-term health status in patients after vascular surgery.

Methods

Between May and December 2004, data on 711 consecutive peripheral arterial disease patients undergoing vascular surgery were collected from 11 hospitals in the Netherlands. Before surgery, the Lee Risk Index was assessed in all patients. At 3-year follow-up, 149 patients died (21%) and the disease-specific Peripheral Artery Questionnaire (PAQ) was completed in 84% (n = 465) of the survivors. Impaired health status according to the PAQ was defined by the lowest tertile of the PAQ summary score. Multivariable regression analyses were performed to investigate the prognostic ability of the Lee Index for mortality and impaired health status at 3-year follow-up.

Results

The Lee Risk Index proved to be an independent prognostic factor for both late mortality (1 risk factor hazard ratio (HR) = 2.1; 95% confidence interval [CI], 1.2-3.6; 2 risk factors HR = 2.4; 95% CI, 1.4-4.0 and ≥3 risk factors HR = 3.2; 95% CI, 1.7-6.2) and impaired health status at 3-year follow-up (1 risk factor odds ratio [OR] = 2.0; 95% CI, 1.1-3.5; 2 risk factors OR = 2.9; 95% CI, 1.6-5.2 and ≥3 risk factors OR = 3.2; 95% CI, 1.3-7.5). The predominant contributing factors associated with late mortality were cerebrovascular disease, insulin-dependent diabetes, and renal insufficiency. For impaired health status, ischemic heart disease, heart failure, cerebrovascular disease, insulin-dependent diabetes, and renal insufficiency were the prognostic factors.

Conclusions

The preoperative Lee Risk Index is not only an important prognostic factor for in-hospital outcome but also for late mortality and impaired health status in patients with peripheral arterial disease.     

Statin therapy in stroke prevention: a meta-analysis involving 121,000 patients

Purpose

More than 120,000 patients now have taken part in randomized trials evaluating statin therapy for stroke prevention. We aimed to conduct a comprehensive review of all randomized trials and determine the therapeutic potential of statins for all strokes.

Methods

We searched 10 electronic databases (from inception to December 2006). We additionally contacted study authors and authors of previous reviews. We extracted data on study characteristics and outcomes related to all-cause mortality, all-stroke incidence, specific type of strokes, and cholesterol changes. We pooled data using a random-effects model and conducted meta-regression.

Results

We included 42 trials assessing statin therapy for all-stroke prevention (n = 121,285), resulting in a pooled relative risk (RR) of 0.84 (95% confidence interval [CI], 0.79-0.91). The pooled RR of statin therapy for all-cause mortality (n = 116,080) was 0.88 (95% CI, 0.83-0.93). Each unit increase in low-density lipoprotein (LDL) resulted in a 0.3% increased RR of death (P = .02). Seventeen trials evaluated statins on cardiovascular death (n = 57,599, RR 0.81, 95% CI, 0.74-0.90), and 11 evaluated nonhemorrhagic cerebrovascular events (n = 58,604, RR 0.81, 95% CI, 0.69-0.94). Eleven trials reported hemorrhagic stroke incidence (total n = 54,334, RR 0.94, 95% CI, 0.68-1.30) and 21 trials reported on fatal strokes (total n = 82,278, RR 0.99, 95% CI, 0.80-1.21). Only one trial reported on statin therapy for secondary prevention.

Conclusions

Statin therapy provides high levels of protection for all-cause mortality and nonhemorrhagic strokes. This overview reinforces the need to consider prolonged statin treatment in patients at high risk of major vascular events, but caution remains for patients at risk of bleeds.     

Raloxifene and Risk for Stroke Based on the Framingham Stroke Risk Score

Purpose

Raloxifene reduces vertebral fracture and invasive breast cancer risks, but increases fatal strokes in postmenopausal women at increased coronary risk. We assessed whether this risk is concentrated in postmenopausal women already at high stroke risk.

Methods

Raloxifene Use for The Heart (RUTH) enrolled 10,101 postmenopausal women (mean age 67 years) with or at increased coronary heart disease risk; Multiple Outcomes of Raloxifene Evaluation (MORE) enrolled 7705 osteoporotic postmenopausal women (mean age 66 years). A Framingham Stroke Risk Score (FSRS) was calculated for all women with no prior cerebrovascular events (n = 16,858). The validity of the FSRS was assessed in the placebo groups, and then raloxifene-associated stroke risk was analyzed by FSRS subgroups.

Results

FSRS predicted an increased stroke risk in the placebo group of both clinical trials. There was no difference in the incidence of nonfatal strokes between the raloxifene and placebo groups in MORE or RUTH, regardless of baseline Framingham stroke risk. In RUTH, women with FSRS <13 showed no increase in raloxifene-associated fatal stroke risk (hazard ratio [HR] 1.08; 95% confidence interval [CI], 0.49-2.37). Those with FSRS ≥13 had a 75% increased risk of raloxifene-associated fatal stroke (HR 1.75; 95% CI, 1.01-3.02; interaction P = .33). In MORE, where 80% of women had a FSRS <13, no increase in fatal (HR 0.57; 95% CI, 0.19-1.68) stroke risk was observed.

Discussion

Risk of fatal stroke associated with raloxifene was greater in women at high stroke risk. These results might be useful for identifying postmenopausal women at high risk of first stroke who should avoid raloxifene therapy.     

Peripheral artery disease and outcomes after myocardial infarction: An individual-patient meta-analysis of 28,771 patients in CAPRICORN,EPEHESUS, OPTIMAAL and VALIANT

Objectives

To examine the prevalence of peripheral artery disease (PAD) and the relationship between PAD and cardiovascular (CV) outcomes in subjects with left ventricular systolic dysfunction, heart failure or both after acute myocardial infarction (MI).

Background

PAD is associated with poorer prognosis in patients with stable and unstable coronary heart disease but whether PAD is associated with worse outcomes following substantial acute MI is unknown.

Methods

Univariate and multivariate Cox proportional hazards modelling was used to compare clinical outcomes in an individual-patient meta-analysis of 4 trials (CAPRICORN, EPHESUS, OPTIMAAL and VALIANT).

Results

Of the 28,771 patients randomized, 2357 (8.2%) had PAD. These patients were older and had more co-morbidity and were less likely to be prescribed aspirin or a beta-blocker compared to patients without PAD. Over a mean follow-up of 2.7 years, 5121 (17.8%) patients died and 15,055 (52.3%) experienced CV death or hospitalization. PAD was an independent predictor of all individual and composite CV outcomes examined (including heart failure), with the exception of stroke. In patients with PAD (compared to those without PAD), the adjusted hazard ratio (HR) for all-cause mortality was 1.25 (95% CI 1.15–1.37; p < 0.001) and the HR for CV death, non-fatal MI, non-fatal stroke or heart failure hospitalization was 1.24 (1.16–1.33; p < 0.001).

Conclusions

PAD is common and is an independent predictor of worse outcomes in patients already at high risk after MI because of left ventricular systolic dysfunction, heart failure or both. These patients represent an important group for intensive application of secondary preventive therapies.     

Aspirin use for the primary prevention of coronary heart disease in older adults

Purpose

Aspirin for the primary prevention of coronary heart disease (has a more favorable risk/benefit profile among adults with high coronary heart disease risk than among low-risk adults, but there is little information on the current patterns of aspirin use for primary prevention. We determined the prevalence of aspirin use in relation to coronary heart disease risk and changes over time.

Subjects and methods

We measured regular aspirin use in 2163 black and white older adults without cardiovascular disease in a population-based cohort from 1997 to 1998 and 2002 to 2003. We determined the 10-year coronary heart disease risk by using the Framingham risk score.

Results

In 1997-1998, 17% of the cohort were regular aspirin users. Aspirin use increased with coronary heart disease risk from 13% in persons with a 10-year risk less than 6% (low risk) to 23% in those with a 10-year risk greater than 20% (highest risk) (P for trend < .001). Blacks were less likely to use aspirin (13%) than whites (20%). In multivariate analysis, black race was still associated with lower aspirin use (odds ratio 0.66, 95% confidence interval 0.49-0.89). In 1997-1998 and 2002 to 2003, aspirin use increased from 17% to 32% among those still free of coronary heart disease (P < .001), and the association with coronary heart disease risk continued (P for trend < .001). Despite their high coronary heart disease risk, diabetic persons were not more likely to use aspirin than nondiabetic persons, even in 2002 and 2003 (odds ratio 0.89, 95% confidence interval 0.56-1.40).

Conclusion

Regular use of aspirin by older adults with no history of cardiovascular disease has increased in recent years. Individuals at higher coronary heart disease risk are more likely to take aspirin, but there is room for considerable improvement in targeting those at high risk, particularly diabetic persons and blacks.     

Long-term Effect of Chronic Oral Anticoagulation with Warfarin after Acute Myocardial Infarction

Background

Antiplatelet therapy is the principal component of the antithrombotic regimen after acute myocardial infarction. It remains unclear whether additional chronic oral anticoagulation (OAC) improves outcomes. We set out to evaluate the risk and benefit of long-term OAC after myocardial infarction.

Methods

We pooled 10 randomized clinical trials comparing warfarin-containing regimens (OAC) with or without aspirin with non-OAC regimens with or without aspirin (No OAC) for patients with recent infarction. The primary endpoint was all-cause mortality. Other endpoints included recurrent infarction, stroke, and major bleeding. We calculated the odds ratio (OR) (fixed effect, OR <1 indicates benefit for OAC) for death and other ischemic and hemorrhagic complications at the longest interval of follow-up available.

Results

Among 24,542 patients, 14,062 were assigned to OAC and 10,480 to no OAC. The patients were followed for 3-63 months, for 89,562 patient-years. Death occurred in 2424 patients (9.9%), 1279 OAC patients, and 1145 in the no OAC group, OR 0.97 (95% confidence interval [CI], 0.88-1.05), P = .43. Similarly, there was no effect on recurrent infarction. Stroke occurred in 578 patients (2.4%), 271 in the OAC group and 307 in the no OAC group, OR 0.75 (95% CI, 0.63-0.89), P = .001. There was substantially more major bleeding (OR 1.83 [95% CI, 1.50-2.23], P <.001) in the OAC group. Separate analyses, performed for patients (n = 11,920) randomized to aspirin versus aspirin and OAC yielded very similar results.

Conclusion

As compared with placebo or aspirin, OAC with or without aspirin does not reduce mortality or reinfarction, reduces stroke, but is associated with significantly more major bleeding.     

Reduction of albumin urinary excretion is associated with reduced cardiovascular events in hypertensive and/or diabetic patients. A meta-regression analysis of 32 randomized trials

Background

The association between renal dysfunction and risk of cardiovascular (CV) events and mortality has been reported in several studies. However, it is unclear whether reduction in urinary albumin excretion (UAE) is associated with reduced risk of clinical events. Therefore, we sought to investigate, in a meta-regression analysis of randomized studies enrolling hypertensive and/or diabetic patients, whether changes in UAE are associated with changes in CV outcomes and all-cause mortality.

Methods

MEDLINE, ISI Web of Science, Cochrane Database and Scopus were searched for randomized trials enrolling more than 200 diabetic and/or hypertensive patients, reporting UAE at baseline and at end of follow-up and CV events [CV death, myocardial infarction (MI), and stroke], as well all-cause mortality.

Results

Thirty-two trials enrolling 80,812 participants were included in analyses. Meta-regression analysis showed that each 10% reduction of UAE was significantly associated with 13% reduction of MI (Regression Coefficient [RC]:0.0055; 95% Confidence Interval [CI]:0.0014 to 0.0095; p = 0.010), with 29% reduction of stroke (RC:0.0124; CI:0.0030 to 0.0218; p = 0.013) and with 14% reduction of the composite outcome (CV death, MI, stroke)(RC:0.0059; CI:0.0027 to 0.0090; p = 0.001), whereas not significantly associated with all-cause (RC:0.0028; CI:− 0.0047 to 0.0103; p = 0.486) and CV mortality (RC:0.0028; CI:− 0.0047 to 0.0103; p = 0.447). Results were mostly confirmed by sensitivity analysis. No heterogeneity or publication bias was detected.

Conclusions

Reduction in UAE is associated with reduced risk of MI and stroke in diabetic and/or hypertensive patients. These findings suggest that UAE changes may represent a valuable intermediate end-point for CV risk evaluation in clinical practice.     

Systematic review and meta-analysis of adverse events of low-dose aspirin and clopidogrel in randomized controlled trials

Purpose

We performed a systematic review to define the relative and absolute risk of clinically relevant adverse events with the antiplatelet agents, aspirin and clopidogrel.

Materials and methods

Databases were searched for randomized controlled trials of low-dose aspirin (75-325 mg/dayay) or clopidogrel administered for cardiovascular prophylaxis. Relative risks (RR) were determined by meta-analysis of 22 trials for aspirin versus placebo and from single studies for aspirin versus clopidogrel, aspirin versus aspirin/clopidogrel, and clopidogrel versus aspirin/clopidogrel. Absolute risk increase was calculated by multiplying RR increase by the pooled weighted incidence of the control.

Results

Aspirin increased the risk of major bleeding (RR = 1.71; 95% confidence interval [CI], 1.41-2.08), major gastrointestinal (GI) bleeding (RR = 2.07; 95% CI, 1.61-2.66), and intracranial bleeding (RR = 1.65; 95% CI, 1.06-5.99) versus placebo. No difference between 75-162.5 mg/day and >162.5-325 mg/day aspirin versus placebo was seen. The absolute annual increases attributable to aspirin were major bleeding: 0.13% (95% CI, 0.08-0.20); major GI bleeding: 0.12% (95% CI, 0.07-0.19), intracranial bleeding: 0.03% (95% CI, 0.01-0.08). No study compared clopidogrel with placebo. One study showed increased major GI bleeding (but not non-GI bleeding endpoints) with aspirin versus clopidogrel (RR = 1.45; 95% CI, 1.00-2.10). The absolute annual increase was 0.12% (95% CI, 0.00-0.28).

Conclusions

Low-dose aspirin increases the risk of major bleeding by ∼70%, but the absolute increase is modest: 769 patients (95% CI, 500-1250) need to be treated with aspirin to cause one additional major bleeding episode annually. Compared with clopidogrel, aspirin increases the risk of GI bleeding but not other bleeding; however, 883 patients (95% CI, 357-∞) would need to be treated with clopidogrel versus aspirin to prevent one major GI bleeding episode annually at a cost of over 1 million dollars.     

High post-clopidogrel platelet reactivity assessed by a point-of-care assay predicts long-term clinical outcomes in patients with ST-segment elevation myocardial infarction who underwent primary coronary stenting

Background

Recent studies have shown that post-clopidogrel high platelet reactivity (HPR), assessed by a point-of-care assay, is associated with a higher risk of adverse events after percutaneous coronary intervention (PCI). We assessed the clinical impact of HPR by the VerifyNow P2Y12 point-of-care assay in 181 patients with ST-segment elevation myocardial infarction (STEMI) who underwent primary PCI with drug-eluting stents (DES) at 3 hospitals.

Methods

The primary endpoint of the study was the 12-month major adverse cardiovascular events (MACE), which comprised cardiovascular death, nonfatal MI and ischemic stroke. All patients received a single loading dose of 600 mg clopidogrel and 300 mg aspirin followed by a daily maintenance dose of 75 mg clopidogrel and 100 mg aspirin.

Results

A P2Y12 reaction unit (PRU) ≥ 282 (AUC 0.719, 95% CI 0.588–0.851, p = 0.004, sensitivity 68.8%, specificity 73.8%) was the optimal cut-off value in predicting 12-month MACE by receiver operating characteristic curve analysis. Occurrence of MACE was significantly more frequent in patients with HPR (PRU ≥ 282) compared to patients without HPR (20.4% vs. 3.9%, HR 6.24, 95% CI 2.05–18.99, p = 0.001). By multivariate analysis, HPR (HR 3.84, 95% CI 1.17–12.58, p = 0.026) and elderly patients above 80 years of age (HR: 8.13, 95% CI 1.79–37.03, p = 0.007) were found to be the significant predictors of 12-month MACE. The MACE-free survival rate was significantly lower in patients with HPR compared to patients without HPR (p < 0.001).

Conclusion

HPR assessed by a point-of-care assay was able to predict 12-month MACE in patients with STEMI who underwent primary PCI with DES.     

Evaluation of a scoring scheme, including proinsulin and the apolipoprotein B/apolipoprotein A1 ratio, for the risk of acute coronary events in middle-aged men: Uppsala Longitudinal Study of Adult Men (ULSAM)

Background

In recent years, the importance of circulating levels of proinsulin and apolipoproteins as risk factors for myocardial infarction (MI) has been highlighted. The aims of the current study were to investigate whether introduction of these new markers of coronary risk could improve the performance of a risk prediction score and to compare this new score with traditional scoring schemes, such as the Framingham Study and the Prospective Cardiovascular Munster (PROCAM) Study schemes.

Methods

From 1970 to 1973 all 50-year-old men in Uppsala, Sweden, were invited to participate in a health survey aimed at identifying risk factors for cardiovascular disease (the Uppsala Longitudinal Study of Adult Men [ULSAM] cohort). The current study investigated metabolic characteristics at baseline and the incidence of fatal and nonfatal MI (n = 251) during 28.7 years of follow-up in 1108 men who were free of coronary heart disease at baseline.

Results

The risk prediction score was derived from one half of the population sample from the ULSAM cohort and included systolic blood pressure, smoking, family history of MI, serum proinsulin, and the ratio between apolipoprotein B and apolipoprotein A1.The score was highly predictive for future MI (hazard ratio, 1.77 for a 1 SD increase; 95% CI, 1.49 to 2.10, P < .0001) in the other half of the population that was not used for generating the score. The ULSAM score performed slightly better than the Framingham and PROCAM scores (evaluated as areas under the receiver operating curves; Framingham, 61%; PROCAM, 63%; ULSAM, 66%; P = .08).

Conclusions

A risk prediction score for MI including proinsulin and the ratio between apolipoprotein B and apolipoprotein A1 was developed in middle-aged men. This score was highly predictive for future fatal and nonfatal MI and proved to be at least as good as the Framingham and the PROCAM scores, being based on traditional risk factors.     

Prognostic value of low-level cardiac troponin-I elevations in patients without definite acute coronary syndromes

Background

Low-level cardiac troponin-I (cTn-I) elevations predict adverse cardiovascular outcomes in patients with definite acute coronary syndromes (ACS), as defined by the presence of chest pain accompanied by ischemic electrocardiographic changes. However, their prognostic value in other clinical situations remains unclear.

Methods

We studied 366 patients with suspected myocardial infarction (MI) but without definite ACS, including 57 patients with low-level cTn-I elevations (1.0 to 3.0 ng/mL) and 309 patients with cTn-I <1.0 ng/mL. All cTn-I measurements were made with the Dade Stratus II analyzer. We determined the adjusted 1-year risk of nonfatal MI or death from coronary heart disease (CHD death) in each group by using Cox proportional hazards models.

Results

Among patients with cTn-I elevations between 1.0 and 3.0 ng/mL, 6 (11%) had a nonfatal MI or CHD death at 1 year compared with 12 (4%) patients in the cTn-I <1.0 ng/mL group [hazard ratio (HR), 3.5; 95% CI, 1.4 to 8.8]. After adjusting for baseline clinical characteristics, cTn-I levels between 1.0 and 3.0 ng/mL remained strongly associated with nonfatal MI or CHD death (adjusted HR, 3.4; 95% CI, 1.3 to 9.4). This association persisted even in the 215 patients who presented without chest pain (adjusted HR, 4.3; 95% CI, 1.4 to 13).

Conclusions

Low-level cTn-I elevations identify a subset of patients at increased risk for future cardiovascular events, even when obtained outside the context of definite ACS or presentation with chest pain.