Marja Puurunen

Anti-Cardiolipin Antibodies and Risk of Myocardial Infarction in a Prospective Cohort of Middle-Aged Men

BACKGROUND Data concerning the relation between antiphospholipid (aPL) antibodies and myocardial infarction in subjects without evidence of overt autoimmune disease are conflicting. All published studies have been performed on survivors of myocardial infarction or in patients with established coronary heart disease. The purpose of the present study was to determine whether the presence of aPL antibodies, namely, anti-cardiolipin (aCL) antibodies, carries a risk for myocardial infarction in a prospective cohort. METHODS AND RESULTS The sera to be studied were drawn at entry from middle-aged dyslipidemic men (non-high-density lipoprotein cholesterol, > or = 5.2 mmol/L) participating in the Helsinki Heart Study, a 5-year coronary primary prevention trial with gemfibrozil. Samples were tested for IgG-class antibodies to cardiolipin by an ELISA. The risk was estimated with logistic regression analysis using a nested case-control design with 133 patients (myocardial infarction or cardiac death) and 133 control subjects, matched for treatment (gemfibrozil/placebo) and geographical area. The aCL antibody level, as expressed in optical density units, was significantly higher in patients than in control subjects (0.417 versus 0.361; P < .005). Subjects with the antibody level in the highest quartile of distribution had a relative risk for myocardial infarction of 2.0 (95% confidence interval, 1.1 to 3.5) compared with the remainder of the population. This risk was independent of confounding factors, such as age, smoking, systolic blood pressure, low-density lipoprotein (LDL), and high-density lipoprotein. There was a correlation between the levels of aCL antibodies and antibodies to oxidized LDL (r = .40, P < .001), and their joint effect was additive for the risk. CONCLUSIONS In a prospective cohort of healthy middle-aged men, the presence of a high aCL antibody level is an independent risk factor for myocardial infarction or cardiac death. Antibodies to cardiolipin and oxidized LDL may, at least in part, represent cross-reactive antibody populations.

Safety of percutaneous coronary intervention during uninterrupted oral anticoagulant treatment

AIMS Uninterrupted anticoagulation (UAC) is assumed to increase bleeding and access-site complications. A common consensus is to postpone percutaneous coronary interventions (PCI) to reach international normalized ratio (INR) levels < 1.5-1.8. METHODS AND RESULTS To assess the safety and feasibility of UAC, we analysed retrospectively all consecutive patients (n = 523) on warfarin therapy referred for PCI in four centres with a policy to interrupt anticoagulation (IAC) before PCI and in three centres with a long experience on UAC during PCI. Major bleeding, access-site complications, and major adverse cardiac events (death, myocardial infarction, target vessel revascularization, and stent thrombosis) were recorded during hospitalization. In the IAC group, warfarin was withdrawn for a mean of 3 days prior to PCI (mean INR 1.7). In the UAC group, mean INR value was 2.2. Glycoprotein IIb/IIIa (GP) inhibitors (P < 0.001) and low-molecular-weight heparins (P < 0.001) were more often used in the IAC group. Major bleeding and access-site complications were more common in the IAC group (5.0% vs. 1.2%, P = 0.02 and 11.3% vs. 5.0%, P = 0.01, respectively) than in the UAC group. After adjusting for propensity score, the group difference in access-site complications remained significant [OR (odds ratio) 2.8, 95% CI (confidence interval) 1.3-6.1, P = 0.008], but did not remain significant in major bleeding (OR 3.9, 95% CI 1.0-15.3, P = 0.05). In multivariable analysis, femoral access (OR 9.9, 95% CI 1.3-75.2), use of access-site closure devices (OR 2.1, 95% CI 1.1-4.0), low-molecular-weight heparin (OR 2.7, 95% CI 1.1-6.7) and old age predicted access-site complications, and the use of GP inhibitors (OR 3.0, 95% CI 1.0-9.1) remained as a predictor of major bleeding. CONCLUSION Our study shows that PCI is a safe procedure during UAC with no excess bleeding complications.

Antibodies to prothrombin crossreact with plasminogen in patients developing myocardial infarction

In a prospective study on healthy middle‐aged men, high level of antibodies to prothrombin implied a risk of myocardial infarction. The possible mechanism(s) of these antibodies in coronary thrombosis are not known. Because prothrombin belongs to the kringle proteins and shares structural homology with a fibrinolytic kringle protein plasminogen, we studied whether antibodies to prothrombin crossreact with plasminogen.

CHADS2, CHA2DS2-VASc and HAS-BLED as predictors of outcome in patients with atrial fibrillation undergoing percutaneous coronary intervention

INTRODUCTION CHADS2 and CHA2DS2-VASc scores are used to estimate thromboembolic risk in atrial fibrillation (AF). HAS-BLED is recommended for bleeding risk prediction. Their value in predicting the outcome of AF patients after percutaneous coronary intervention (PCI) is unknown. Thus, our aim was to assess whether these simple risk scores are useful in predicting outcome in these patients. MATERIALS AND METHODS AFCAS is an observational, multicenter, prospective registry including patients (n=929) with AF referred for PCI. Primary study endpoints were 1) all cause mortality; 2) major adverse events (all-cause mortality, myocardial infarction, repeat revascularization, stent thrombosis, transient ischemic attack, stroke or other arterial thromboembolism; MACCE); and 3) bleeding at 12 months follow-up. CHADS2 and CHA2DS2-VASc scores and a modified HAS-BLED (mHAS-BLED) score (omitting labile INR and liver function) were calculated. RESULTS Patients were distributed as follows: CHADS2 low 29.5%, intermediate 55.2%, high 15.3%; CHA2DS2-VASc low 9.6%, intermediate 46.0%, high 44.5%. A high CHA2DS2-VASc score was predictive of all-cause mortality (p=0.02), whereas CHADS2 was not. High CHA2DS2-VASc score predicted MACCE (HR 2.24, 95%CI 1.21-4.17, p=0.01), as did a high CHADS2 score (HR 1.60, 95%CI 1.05-2.45, p=0.029). Their predictive performance was only modest (C indexes 0.56-0.57). CHADS2 or CHA2DS2-VASc scores were not associated with bleeding. High mHAS-BLED scores (≥3) were not associated with any of the study outcomes. CONCLUSIONS High CHA2DS2-VASc score was the best predictor of thrombotic outcomes after PCI in a high risk AF population. High mHAS-BLED score was not predictive of bleeding events. More accurate, simple risk scores are needed.

Persistent antiphospholipid antibody (aPL) in asymptomatic carriers as a risk factor for future thrombotic events: a nationwide prospective study

Objectives The long-term prognosis of individuals fulfilling the laboratory criteria, but not clinical criteria, of antiphospholipid syndrome (APS) has not been widely investigated. The primary aim of this study was to evaluate the incidence of first thrombotic event (deep venous thrombosis (DVT), pulmonary embolism (PE), myocardial infarction (MI), stroke or transient ischaemic attack (TIA) in a nationwide antiphospholipid antibody (aPL) carrier cohort. Design We conducted a prospective nationwide cohort study. Setting The aPL profile of participants was recorded from the laboratory database. Information was collected about thrombotic and pregnancy complications, subsequent medical history, other risk factors for thrombosis, use of prophylactic antithrombotic medication and general health. Participants Participants included adult asymptomatic aPL carriers recognized in Finland during 1971–2009. Main outcome measure The main outcome measure was incidence of first thrombotic event. Results A total of 119 (89% female) aPL carriers were followed for mean (SD) of 9.1 (7.5) years (range 3–41 years). Sixty-one per cent of the study participants had autoimmune disease, most often systemic lupus erythematosus (SLE). Thirty-six of 119 (30%) were either double or triple positive, 56% single lupus anticoagulant (LA) positive, and 8% and 5% single anticardiolipin antibodies (aCL) and anti-β2glycoprotein I antibodies (aβ2GPI) positive, respectively. Nine (7.6%) study patients experienced a first thrombotic event (five DVT, one PE, two MI, one TIA) mean (SD) 7.2 (8.3) years (range 1–26 years) after aPL detection (annual incidence rate 0.8%). All individuals who developed thrombotic complications had autoimmune disease. Annual rate of first thrombotic event in carriers of single positivity (0.65%) was equal to the known risk of thrombosis in the healthy Caucasian population, whereas the rate was two times higher in carriers of double or triple positivity (1.27%). Sixteen of 79 (20%) women experienced pregnancy complications. Conclusions Double or triple positivity for aPL is a risk factor for future thrombotic events, especially in individuals with an underlying autoimmune disease, whereas single positivity does not seem to carry an elevated risk of thrombosis.

Are glycoprotein inhibitors safe during percutaneous coronary intervention in patients on chronic warfarin treatment

The aim of this study was to evaluate the safety of glycoprotein IIb/IIIa inhibitors (GPIs) during percutaneous coronary intervention (PCI) in patients on chronic warfarin therapy due to atrial fibrillation (AF). We analysed all consecutive AF patients (N = 377, mean age 70 years, male 71%) on warfarin therapy referred for PCI in seven centres. Major bleeding, access site complications and major adverse cardiovascular events were recorded during hospitalisation. A total of 111 patients (29%) received periprocedural GPIs with a wide inter-hospital variation in their use (range 3-68%). The use of GPIs increased with the severity of the disease presentation and 49% of patients with ST-elevation myocardial infarction received GPIs. Mean periprocedural international normalised ratio (INR) of patients who received GPIs was 1.89 (range 1.1-3.3). Major bleeding was more common in the patients treated with GPIs (9.0% vs. 1.5%, p = 0.001) than in those without GPIs, but there was no difference in major adverse cardiovascular events between the groups. In multivariable analysis, use of GPIs (odds ratio [OR] 5.1, 95% confidence interval [CI] 1.3-20.6, p = 0.02) and old age (OR 1.2, 95% CI 1.0-1.3, p= 0.02) remained as the only independent predictors of major bleeding. Also after adjusting for propensity score, GPIs remained as a significant predictor of major bleeding (OR 3.8, 95% CI 1.03-14.1, p = 0.045). In the GPI group, major bleeding was not predicted by INR level or warfarin pause. GPIs increase the risk of major bleeding events irrespective of periprocedural INR levels and should be used with caution in this fragile patient group.

Epidemiology of venous thromboembolism in the Framingham Heart Study

BACKGROUND Reports of the crude incidence of venous thromboembolism (VTE) in Western countries vary widely. Data regarding risk factors, incidence and recurrence of VTE from deeply-phenotyped community-based cohort studies are needed. OBJECTIVES To study the incidence, associated mortality, and predisposing factors of VTE in the prospective, longitudinal community-based Framingham Heart Study. PATIENTS/METHODS The study sample consisted of the Framingham Heart Study Original, Offspring, Third Generation, and Omni cohorts (N=9754). Incidence rates (IR) were standardized to the 2000 US population. Cox proportional hazards regression models were used to study risk factor associations. RESULTS During 1995-2014 (total follow-up time 104,091 person-years [median 9.8 (range 0-20) years]), 297 incident VTE events were observed. Age-adjusted IR of VTE was 20.3/10,000 (95% CI 17.9-22.6). Of the events 120 (40%) were pulmonary embolism (PE) and 177 (60%) were deep venous thrombosis (DVT); 29% were unprovoked, 40% provoked, and 31% cancer-related. Cancer-related VTE was associated with high mortality at 30days (24.2%), 1year (66.3%), and 5years (75.6%). In multivariable models, age and obesity, but no other traditional cardiovascular risk factors, were significantly associated with VTE (hazard ratio [HR] per 10-year increase in age 1.69, 95% CI 1.48-1.92; HR for obesity (BMI≥30kg/m(2)) 1.88, 95% CI 1.44-2.45). CONCLUSIONS We provide data on the epidemiology of VTE. VTE is associated with significant mortality, and prognosis after cancer-related VTE is particularly poor. Traditional cardiovascular risk factors beyond age and obesity are not associated with VTE.

Performance of Bleeding Risk-Prediction Scores in Patients With Atrial Fibrillation Undergoing Percutaneous Coronary Intervention

The hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, and drugs/alcohol (HAS-BLED); anticoagulation and risk factors in atrial fibrillation (ATRIA); modified Outpatient Bleeding Risk Index (mOBRI); and reduction of atherothrombosis for continued health (REACH) schemes are validated bleeding risk-prediction tools, but their predictive performance in patients with AF receiving multiple antithrombotic drugs after percutaneous coronary intervention (PCI) is unknown. We sought to compare the predictive performance of bleeding risk-estimation tools in a cohort of patients with atrial fibrillation (AF) undergoing PCI. Management of patients with AF undergoing coronary artery stenting is a multicenter European prospective registry enrolling patients with AF undergoing PCI. We calculated HAS-BLED, ATRIA, mOBRI, and REACH bleeding risk-prediction scores and assessed the rate of bleeding complications as defined by Bleeding Academic Research Consortium at 12 months follow-up in 929 consecutive patients undergoing PCI. Increasing age, femoral access site, and previous peptic ulcer were independent determinants of bleeding. Low bleeding risk scores as determined by HAS-BLED 0 to 2, ATRIA 0 to 3, mOBRI 0, and REACH 0 to 10 were detected in 23.7%, 73.0%, 7.8%, and 5.7% of patients of the cohort, respectively. No significant differences were detected in the rates of any bleeding or major bleeding events for low versus intermediate/high scores with each risk-prediction tool. In conclusion, the performance of ATRIA, HAS-BLED, mOBRI, and REACH scores in predicting bleeding complications in this high-risk patient subset was useless.

Usefulness of Outpatient Bleeding Risk Index to Predict Bleeding Complications in Patients With Long-term Oral Anticoagulation Undergoing Coronary Stenting

Long-term oral anticoagulation (OAC) prevents recurrent thrombosis, pulmonary embolism, and stroke, but it also increases bleeding risk. An outpatient bleeding risk index (OBRI) may help to identify patients at high risk of bleeding complications. The aim of this study was to evaluate the predictive value of OBRI in patients with OAC undergoing percutaneous coronary intervention (PCI). In addition, we analyzed the impact of OBRI on treatment choices in this patient group. Four hundred twenty-one patients with OAC underwent PCI at 6 centers in Finland. Complete follow-up was achieved in all patients (median 1,276 days). Sixty-four patients (15%) had a low bleeding risk (OBRI 0), 319 patients (76%) moderate bleeding risk (OBRI 1 to 2), and 38 (9%) high bleeding risk (OBRI 3 to 4). OBRI had no significant effect on periprocedural or long-term antithrombotic medications, choice of access site, or stent type. During follow-up, the incidence of major bleeding increased (p = 0.02) progressively with higher OBRI category (6.3%, 14.1%, and 26.3%, respectively). Similarly, mortality was highest in patients with high OBRI (14.1%, 20.7%, and 39.5%, p = 0.009, respectively), but rates of major adverse cardiovascular and cerebrovascular events were comparable in the OBRI categories. In conclusion, bleeding risk seems not to modify periprocedural or long-term treatment choices in patients after PCI on home warfarin. In contrast, patients with high OBRI often have major bleeding episodes and this simple index seems to be suitable for risk evaluation in this patient group.

Comparison of Additional Versus No Additional Heparin During Therapeutic Oral Anticoagulation in Patients Undergoing Percutaneous Coronary Intervention

Uninterrupted oral anticoagulation (OAC) therapy can be the preferred strategy in patients with atrial fibrillation at moderate to high risk of thromboembolism undergoing percutaneous coronary intervention (PCI). To evaluate the need for additional heparins in addition to therapeutic peri-PCI OAC, we assessed bleeding complications and major adverse cardiac and cerebrovascular events in 414 consecutive patients undergoing PCI during therapeutic (international normalized ratio 2 to 3.5) periprocedural OAC. Patients were divided into those with no (n = 196) and with (n = 218) additional use of periprocedural heparins. No differences in major adverse cardiac and cerebrovascular events (4.1% vs 3.2%, p = 0.79) or major bleeding (1.0% vs 3.7%, p = 0.11) were detected, but access site complications (5.1% vs 11.0%, p = 0.032) were less frequent in those without additional heparins. When adjusted for propensity score, patients with additional heparins had a higher risk of access site complications (odds ratio 2.6, 95% confidence interval 1.1 to 6.1, p = 0.022) without any increased risk of any other adverse event. Analysis of 1-to-1 propensity-matched pairs showed a significantly higher risk of access site complication in patients receiving additional AC (13.1% vs 5.7%, p = 0.049). In conclusion, therapeutic warfarin treatment seems to provide sufficient AC for PCI. Additional heparins are not needed and may increase access site complications.