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Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism
ST-segment resolution but was associated with more transfusions and non-cerebral bleeding. Perspective: Two recent large scale studies, GUSTO V and ASSENT 3, have failed to show mortality benefit with the combination of abciximab and thrombolytic therapy, although reinfarction rates were reduced. It remains to be seen whether the beneficial angiographic effects of the combination of double bolus eptifibatide plus half-dose TNK observed in this study translate into mortality benefit in a large-scale randomized clinical trial. RM
ever, until such data are available, many experts believe that patients with STEMI 75 years or older should be treated with primary percutaneous coronary intervention, and in the absence of such a facility, with fibrinolytic agents if not contraindicated. RM
Statins Are Associated With a Reduced Incidence of Perioperative Mortality in Patients Undergoing Major Noncardiac Vascular Surgery Poldermans D, Bax JJ, Kertai MD, et al. Circulation 2003;107: 1848 –51.
Fibrinolytic Therapy in Patients 75 Years and Older With ST-Segment-Elevation Myocardial Infarction. One-Year Follow-up of a Large Prospective Cohort
Study Question: Do inhibitors of the 3-hydroxy-3-methylglutaryl coenzyme A (statins) reduce perioperative mortality in patients undergoing major vascular surgery? Methods: A case-controlled study among the 2816 patients who underwent major vascular surgery from 1991 to 2000 at the Erasmus Medical Center was performed to evaluate the association between statin use and perioperative mortality. Patients who died during hospital stay after surgery (cases, n⫽160 [5.8%]) patients were compared with controls from the remaining subjects, two controls being selected for each case stratified according to calendar year and type of surgery. Information was obtained for both groups regarding the presence of cardiac risk factors and the use of cardiovascular medications (including statins) before surgery. Results: Death from a vascular complication during the perioperative phase occurred in 65% of case subjects. Statin use was significantly less common in cases than in controls (8% vs. 25%; p⫽0.001). Perioperative mortality was lower among statin users as compared with nonusers (adjusted odds ratio 0.22, 95% confidence interval 0.10 – 0.47). Similar benefit of statin use was observed in subgroups of patients according to the use of cardiovascular therapy and the presence of cardiac risk factors. Conclusions: This case-controlled study suggests that statin use reduces perioperative mortality in patients undergoing major vascular surgery. Perspective: Statins have long been shown to be effective for secondary prevention of cardiovascular disease and are indicated in patients with vascular disease, irrespective of whether they are undergoing vascular surgery or not. Hence, the low rates of statins (8% in case and 25% in controls) seen in this study should stimulate physicians to increase their use. RM
Stenestrand U, Wallentin L, for the Register of Information and Knowledge about Swedish Heart Intensive Care Admissions (RIKS-HIA). Arch Intern Med 2003;163:965–71. Study Question: What are the risks/benefits of fibrinolytic therapy in patients with acute ST-elevation myocardial infarction (STEMI) in patients who are 75 years and older? Methods: The RIKS-HIA recorded every patient admitted to a coronary care unit in 64 hospitals during 1995 to 1999. The relationship between 1-year mortality (obtained by merging the RIKS-HIA data with the National Cause of Death Register) and bleeding in STEMI was evaluated using propensity (adjusting for multiple factors known to influence fibrinolytic therapy) and Cox regression analysis (adjusting for factors affecting survival). Results: A total of 3897 of 6891 patients over age 75 years received fibrinolytic therapy. Propensity score analysis identified age, use of oral anticoagulation on admission, history of prior stroke, sites with cardiac catheterization facility, hospital size, circulatory arrest on arrival, congestive heart failure, renal failure, use of diuretics before inclusion, diabetes, cancer within last 3 years, use of angiotensinconverting enzyme inhibitor before admission and previous MI (c statistics 0.66) with lower likelihood of receiving fibrinolytic therapy. After adjusting for covariates, including propensity score, fibrinolytic therapy was associated with lower 1-year mortality and nonfatal cerebral bleeding rate among elderly patients with STEMI (32% vs. 36%, relative risk 0.87, 95% confidence interval 0.80 – 0.94; p⫽0.001). Conclusions: In patients age 75 years or older, fibrinolytic therapy in patients with STEMI is associated with a lower incidence of 1-year death and cerebral bleeding rate (composite), supporting the use of these agents in this cohort. Perspective: Thrombolytic therapy was given to low-risk patients as demonstrated by the propensity analysis. Despite adjustments for 29 covariates and propensity scores, it is unlikely that such adjustments could account for all confounders, particularly those not measured. As such, the beneficial effects of fibrinolytic therapy in this age group needs to be confirmed in randomized clinical trials. How-
Long-Term, Low-Intensity Warfarin Therapy for the Prevention of Recurrent Venous Thromboembolism Ridker P, Goldhaber SZ, Danielson E, et al., for the PREVENT Investigators. N Engl J Med 2003;348:1425–34. Study Question: Is there a value to long-term and lowintensity warfarin for the prevention of recurrent venous thrombosis and/or pulmonary emboli (VTE) in men and
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Methods: BNP was obtained at presentation in 110 consecutive patients with a PE documented by high probability V/Q scan, helical CT or pulmonary angiography or nonhigh probability V/Q with evidence for leg venous thrombosis. Patients requiring thrombolytic therapy and renal insufficiency were excluded. Deaths were adjudicated at 3 months as due to PE, related to PE and all-cause mortality. Positive and negative predictive value of BNP for predicting death was calculated for the highest and lowest tertile. BNP was determined by immunoradiometric assay with a normal range of 0.4 – 4.6 pmol/L. Results: The mean age was 58 years. The median BNP was 9.4 pmol/L (range 1.7–37.1). 10% of patients died by 3 months, seven related to PE of which five were definite. The remaining 4 deaths were attributable to cancer. There was no difference between survivors and non-survivors regarding prevalence of COPD or CV disease. The mean BNP among survivors was 8.7 pmol/L (range 1.5 to 29.3) compared to 71.6 pmol/L (range 47.1 to 117.1) in those who died. The risk of death related to PE with a BNP ⬎21.7 pmol/L was 17% and the negative predictive value of a BNP ⬍21.7 pmol/L was 99%. Conclusions: BNP levels obtained at presentation appear to predict adverse outcome in patients with acute pulmonary embolism. Perspective: The results are not surprising since the BNP reflects the right ventricular hemodynamic burden and also may reflect increased LV wall stress. Cardiac troponins (cTnI and cTnT) are also predictors of a poor outcome in PE reflecting RV and or LV myonecrosis. Despite several trials, it is still challenging to identify those who would benefit from thrombolysis. Future trials will be needed to determine whether the BNP level on presentation can help facilitate the correct use of thrombolytic therapy or percutaneous embolectomy. MR
women with idiopathic VTE with or without thrombophilic mutations such as Factor V Leiden, the prothrombin G20210A polymorphism or increased homocysteine? Methods: 508 patients with documented idiopathic VTE (not associated with surgery, trauma or pregnancy) within the previous 2 years and previously treated for at least 12 weeks with full-dose warfarin were enrolled. Patients were randomized to placebo or low-intensity warfarin (warfarin) to a target INR of 1.5–2.0 using a finger stick device. Primary end points were bleeding risk on warfarin and recurrent venous thromboembolism. Exclusion criteria included age ⬍30 years, cancer, history of bleeding or stroke, lupus anticoagulant or antiphospholipid antibodies or requirement for antiplatelets or other antithrombotic agents. Results: The average age was 53 years, 47% were women, 86% white, 38% had at least 2 previous bouts of VTE, 24% had Factor V Leiden, 5% a prothrombin mutation, and the mean duration of warfarin prior to enrollment was 6.5 months. The median time between cessation of full-dose warfarin and enrollment was 1.7 months (interquartile 0.9 –5 months). The trial was terminated after 508 patients had undergone randomization treatment for a mean of 2.1 years (maximal 4.3 years). 37 of 253 placebo patients has a recurrent VTE (7.2 per 100 person-years), as compared to 14 of 255 patients on warfarin (2.6 per 100 person-years), a 64% reduction (RR 0.36, 95% CI 0.19 – 0.67, p⬍0.001. The benefit was similar across subgroups including those with thrombophilia, the exception being those with a VTE more than 1 year earlier. Major hemorrhage occurred in two patients on placebo and five on warfarin, p⫽0.25, and there was no difference in mortality. Warfarin was associated with a 48% reduction in the composite end point of recurrent VTE, major hemorrhage or death. Conclusions: Long-term, low-intensity warfarin therapy is a highly effective method of preventing recurrent venous thromboembolism. Perspective: The PREVENT investigators are to be congratulated for this sentinel study. Clinicians reading the same literature have concluded for and against long-term anticoagulation in VTE. There seems little question now for idiopathic VTE. Several questions remain unanswered however: (1) the risk to benefit of an INR target of 1.5 to 2 vs. 2 to 3, (2) how long to treat and (3) the benefit in persons with a history of VTE more than 1 year earlier. MR
C-Reactive Protein and Future Risk of Thromboembolic Stroke in Healthy Men Curb JD, Abbott RD, Rodriquez BL, et al. Circulation 2003;107: 2016 –20. Study Question: Does hs-CRP influence or predict the risk of future thromboembolic strokes in asymptomatic middleaged and older men? Methods: A nested case-control study of 259 cases of stroke identified in the Honolulu Heart Program (HHP), in which over 8000 Japanese American men between 45 and 68 years living in Hawaii were followed for 20 years. This study compared the CRP in incident stroke cases with that in 1348 controls randomly selected from the remaining 4145 men free of stroke and coronary heart disease. Enrollment was in late 1960s when serum was frozen at ⫺20°C, transferred to ⫺70°C in 1980, and thawed for CRP determination by an ELISA. Strokes included atherothrombotic and embolic events.
Brain Natriuretic Peptide as a Predictor of Adverse Outcome in Patients with Pulmonary Embolism ten Wolde M, Tulevski II, Mulder JSW, et al. Circulation 2003; 107:2082– 4. Study Question: Is plasma brain natriuretic peptide (BNP), a novel neuropeptide marker of right and left ventricular wall stress and dysfunction, a predictor of mortality in acute pulmonary embolism (PE)?
ACC CURRENT JOURNAL REVIEW Jul/Aug 2003
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ever, until such data are available, many experts believe that patients with STEMI 75 years or older should be treated with primary percutaneous coronary intervention, and in the absence of such a facility, with fibrinolytic agents if not contraindicated. RM
Statins Are Associated With a Reduced Incidence of Perioperative Mortality in Patients Undergoing Major Noncardiac Vascular Surgery Poldermans D, Bax JJ, Kertai MD, et al. Circulation 2003;107: 1848 –51.
Fibrinolytic Therapy in Patients 75 Years and Older With ST-Segment-Elevation Myocardial Infarction. One-Year Follow-up of a Large Prospective Cohort
Study Question: Do inhibitors of the 3-hydroxy-3-methylglutaryl coenzyme A (statins) reduce perioperative mortality in patients undergoing major vascular surgery? Methods: A case-controlled study among the 2816 patients who underwent major vascular surgery from 1991 to 2000 at the Erasmus Medical Center was performed to evaluate the association between statin use and perioperative mortality. Patients who died during hospital stay after surgery (cases, n⫽160 [5.8%]) patients were compared with controls from the remaining subjects, two controls being selected for each case stratified according to calendar year and type of surgery. Information was obtained for both groups regarding the presence of cardiac risk factors and the use of cardiovascular medications (including statins) before surgery. Results: Death from a vascular complication during the perioperative phase occurred in 65% of case subjects. Statin use was significantly less common in cases than in controls (8% vs. 25%; p⫽0.001). Perioperative mortality was lower among statin users as compared with nonusers (adjusted odds ratio 0.22, 95% confidence interval 0.10 – 0.47). Similar benefit of statin use was observed in subgroups of patients according to the use of cardiovascular therapy and the presence of cardiac risk factors. Conclusions: This case-controlled study suggests that statin use reduces perioperative mortality in patients undergoing major vascular surgery. Perspective: Statins have long been shown to be effective for secondary prevention of cardiovascular disease and are indicated in patients with vascular disease, irrespective of whether they are undergoing vascular surgery or not. Hence, the low rates of statins (8% in case and 25% in controls) seen in this study should stimulate physicians to increase their use. RM
Stenestrand U, Wallentin L, for the Register of Information and Knowledge about Swedish Heart Intensive Care Admissions (RIKS-HIA). Arch Intern Med 2003;163:965–71. Study Question: What are the risks/benefits of fibrinolytic therapy in patients with acute ST-elevation myocardial infarction (STEMI) in patients who are 75 years and older? Methods: The RIKS-HIA recorded every patient admitted to a coronary care unit in 64 hospitals during 1995 to 1999. The relationship between 1-year mortality (obtained by merging the RIKS-HIA data with the National Cause of Death Register) and bleeding in STEMI was evaluated using propensity (adjusting for multiple factors known to influence fibrinolytic therapy) and Cox regression analysis (adjusting for factors affecting survival). Results: A total of 3897 of 6891 patients over age 75 years received fibrinolytic therapy. Propensity score analysis identified age, use of oral anticoagulation on admission, history of prior stroke, sites with cardiac catheterization facility, hospital size, circulatory arrest on arrival, congestive heart failure, renal failure, use of diuretics before inclusion, diabetes, cancer within last 3 years, use of angiotensinconverting enzyme inhibitor before admission and previous MI (c statistics 0.66) with lower likelihood of receiving fibrinolytic therapy. After adjusting for covariates, including propensity score, fibrinolytic therapy was associated with lower 1-year mortality and nonfatal cerebral bleeding rate among elderly patients with STEMI (32% vs. 36%, relative risk 0.87, 95% confidence interval 0.80 – 0.94; p⫽0.001). Conclusions: In patients age 75 years or older, fibrinolytic therapy in patients with STEMI is associated with a lower incidence of 1-year death and cerebral bleeding rate (composite), supporting the use of these agents in this cohort. Perspective: Thrombolytic therapy was given to low-risk patients as demonstrated by the propensity analysis. Despite adjustments for 29 covariates and propensity scores, it is unlikely that such adjustments could account for all confounders, particularly those not measured. As such, the beneficial effects of fibrinolytic therapy in this age group needs to be confirmed in randomized clinical trials. How-
Long-Term, Low-Intensity Warfarin Therapy for the Prevention of Recurrent Venous Thromboembolism Ridker P, Goldhaber SZ, Danielson E, et al., for the PREVENT Investigators. N Engl J Med 2003;348:1425–34. Study Question: Is there a value to long-term and lowintensity warfarin for the prevention of recurrent venous thrombosis and/or pulmonary emboli (VTE) in men and
ACC CURRENT JOURNAL REVIEW Jul/Aug 2003
13
Methods: BNP was obtained at presentation in 110 consecutive patients with a PE documented by high probability V/Q scan, helical CT or pulmonary angiography or nonhigh probability V/Q with evidence for leg venous thrombosis. Patients requiring thrombolytic therapy and renal insufficiency were excluded. Deaths were adjudicated at 3 months as due to PE, related to PE and all-cause mortality. Positive and negative predictive value of BNP for predicting death was calculated for the highest and lowest tertile. BNP was determined by immunoradiometric assay with a normal range of 0.4 – 4.6 pmol/L. Results: The mean age was 58 years. The median BNP was 9.4 pmol/L (range 1.7–37.1). 10% of patients died by 3 months, seven related to PE of which five were definite. The remaining 4 deaths were attributable to cancer. There was no difference between survivors and non-survivors regarding prevalence of COPD or CV disease. The mean BNP among survivors was 8.7 pmol/L (range 1.5 to 29.3) compared to 71.6 pmol/L (range 47.1 to 117.1) in those who died. The risk of death related to PE with a BNP ⬎21.7 pmol/L was 17% and the negative predictive value of a BNP ⬍21.7 pmol/L was 99%. Conclusions: BNP levels obtained at presentation appear to predict adverse outcome in patients with acute pulmonary embolism. Perspective: The results are not surprising since the BNP reflects the right ventricular hemodynamic burden and also may reflect increased LV wall stress. Cardiac troponins (cTnI and cTnT) are also predictors of a poor outcome in PE reflecting RV and or LV myonecrosis. Despite several trials, it is still challenging to identify those who would benefit from thrombolysis. Future trials will be needed to determine whether the BNP level on presentation can help facilitate the correct use of thrombolytic therapy or percutaneous embolectomy. MR
women with idiopathic VTE with or without thrombophilic mutations such as Factor V Leiden, the prothrombin G20210A polymorphism or increased homocysteine? Methods: 508 patients with documented idiopathic VTE (not associated with surgery, trauma or pregnancy) within the previous 2 years and previously treated for at least 12 weeks with full-dose warfarin were enrolled. Patients were randomized to placebo or low-intensity warfarin (warfarin) to a target INR of 1.5–2.0 using a finger stick device. Primary end points were bleeding risk on warfarin and recurrent venous thromboembolism. Exclusion criteria included age ⬍30 years, cancer, history of bleeding or stroke, lupus anticoagulant or antiphospholipid antibodies or requirement for antiplatelets or other antithrombotic agents. Results: The average age was 53 years, 47% were women, 86% white, 38% had at least 2 previous bouts of VTE, 24% had Factor V Leiden, 5% a prothrombin mutation, and the mean duration of warfarin prior to enrollment was 6.5 months. The median time between cessation of full-dose warfarin and enrollment was 1.7 months (interquartile 0.9 –5 months). The trial was terminated after 508 patients had undergone randomization treatment for a mean of 2.1 years (maximal 4.3 years). 37 of 253 placebo patients has a recurrent VTE (7.2 per 100 person-years), as compared to 14 of 255 patients on warfarin (2.6 per 100 person-years), a 64% reduction (RR 0.36, 95% CI 0.19 – 0.67, p⬍0.001. The benefit was similar across subgroups including those with thrombophilia, the exception being those with a VTE more than 1 year earlier. Major hemorrhage occurred in two patients on placebo and five on warfarin, p⫽0.25, and there was no difference in mortality. Warfarin was associated with a 48% reduction in the composite end point of recurrent VTE, major hemorrhage or death. Conclusions: Long-term, low-intensity warfarin therapy is a highly effective method of preventing recurrent venous thromboembolism. Perspective: The PREVENT investigators are to be congratulated for this sentinel study. Clinicians reading the same literature have concluded for and against long-term anticoagulation in VTE. There seems little question now for idiopathic VTE. Several questions remain unanswered however: (1) the risk to benefit of an INR target of 1.5 to 2 vs. 2 to 3, (2) how long to treat and (3) the benefit in persons with a history of VTE more than 1 year earlier. MR
C-Reactive Protein and Future Risk of Thromboembolic Stroke in Healthy Men Curb JD, Abbott RD, Rodriquez BL, et al. Circulation 2003;107: 2016 –20. Study Question: Does hs-CRP influence or predict the risk of future thromboembolic strokes in asymptomatic middleaged and older men? Methods: A nested case-control study of 259 cases of stroke identified in the Honolulu Heart Program (HHP), in which over 8000 Japanese American men between 45 and 68 years living in Hawaii were followed for 20 years. This study compared the CRP in incident stroke cases with that in 1348 controls randomly selected from the remaining 4145 men free of stroke and coronary heart disease. Enrollment was in late 1960s when serum was frozen at ⫺20°C, transferred to ⫺70°C in 1980, and thawed for CRP determination by an ELISA. Strokes included atherothrombotic and embolic events.
Brain Natriuretic Peptide as a Predictor of Adverse Outcome in Patients with Pulmonary Embolism ten Wolde M, Tulevski II, Mulder JSW, et al. Circulation 2003; 107:2082– 4. Study Question: Is plasma brain natriuretic peptide (BNP), a novel neuropeptide marker of right and left ventricular wall stress and dysfunction, a predictor of mortality in acute pulmonary embolism (PE)?
ACC CURRENT JOURNAL REVIEW Jul/Aug 2003
14