Thrombosis prevention trial: compliance with warfarin treatment and investigation of a retained effect

BACKGROUND: The Thrombosis Prevention Trial was a primary prevention factorial trial that reported a reduction in the risk of coronary heart disease (CHD) with warfarin and/or aspirin. This article examines compliance (duration of treatment) with warfarin treatment and whether warfarin has a retained effect. METHODS: Risk of CHD while complying with warfarin treatment was compared with risk of CHD in all participants randomized to placebo. Simultaneously, risk of CHD in ex-warfarin users was compared with controls receiving placebo to determine the possibility of a retained effect. A second analysis, preserving the advantage of randomization, estimated the potential increase in the time to a CHD event in patients randomized to active treatment compared with patients randomized to placebo, if all patients in both active and placebo groups had fully complied with the trial treatment. RESULTS: Risk of all CHD while complying with warfarin treatment was associated with a hazard ratio (HR) of 0.75 (95% confidence interval [CI], 0.60-0.94), which was lower than the HR obtained by intention-to-treat analysis (0.79; 95% CI, 0.65-0.96). Regarding fatal cases of CHD, the HR was 0.49 (95% CI, 0.32-0.75) while compliant with warfarin treatment, which is also lower than the HR obtained by intention-to-treat analysis (0.61, 95% CI, 0.43-0.85). Ex-warfarin users had a retained risk reduction of 23% for all CHD (0.77; 95% CI, 0.58-1.02) and of 34% for fatal events (0.66; 95% CI, 0.41-1.04). Expected survival time to a CHD event if patients randomized to warfarin had fully complied with treatment was 1.39 times greater (95% CI, 1.12-1.69) than if patients randomized to placebo had fully complied with placebo, whereas for fatal CHD the relative increase in survival time was 2.04 times greater for the former (95% CI, 1.43-2.86). CONCLUSIONS: Full compliance with warfarin treatment may lower by 50% the risk of fatal CHD. There is also evidence of a retained effect. These results strengthen previous evidence of the potential benefits of low-intensity oral anticoagulation with warfarin.     

Aspirin in the primary prevention of angina pectoris in a randomized trial of United States physicians

PURPOSE: The objective of this study was to examine the effect of low-dose aspirin (325 mg on alternate days) on the primary prevention of angina pectoris in the United States Physicians' Health Study. Despite a postulated role of platelets in atherogenesis and myocardial ischemia, the effect of chronic platelet inhibition on the development of clinical angina pectoris is unknown. SUBJECTS AND METHODS: The Physicians' Health Study is a randomized, double-blind, placebo-controlled trial among 22,071 male physicians aged 40 to 84 years, free from previous myocardial infarction, stroke, and transient cerebral ischemia at entry, and followed for an average of 60.2 months. The 21,738 physicians who were also free from angina pectoris at baseline constituted the study population for the present analyses. RESULTS: During 106,652 person-years of follow-up, 331 patients with confirmed angina pectoris were diagnosed, 194 of whom underwent a coronary revascularization procedure (coronary artery bypass graft surgery or coronary angioplasty). As compared to participants assigned placebo, the relative risk of confirmed angina pectoris in the aspirin group was 1.10 (95% confidence interval [CI], 0.88 to 1.38). For coronary revascularization, the relative risk was 1.19 (95% CI, 0.88 to 1.59). After simultaneous control for other coronary risk factors in a proportional-hazards model, these relative risks remained near unity at 1.07 (95% CI, 0.84 to 1.36) and 1.11 (95% CI, 0.81 to 1.52), respectively. When the risks of angina pectoris were examined according to year of randomization in the trial, there was no pattern of increasing benefit with longer duration of treatment. CONCLUSION: These randomized trial data indicate that chronic platelet inhibition with low-dose aspirin for an average duration of 60.2 months does not reduce the incidence of angina pectoris.     

Verapamil treatment after coronary angioplasty in patients at high risk of recurrent stenosis.

OBJECTIVE--To evaluate the efficacy of high-dose verapamil treatment (240 mg twice daily) in the prevention of angiographic restenosis after primary successful coronary angioplasty in patients at high risk of recurrent obstruction. DESIGN--A placebo controlled, double blind trial in which patients with stable angina pectoris and patients with unstable angina or non-Q wave infarction treated with 330 mg aspirin and 75 mg dipyridamole twice daily were randomised to a verapamil group or a control group. Follow up angiography was performed 6 months after angioplasty or sooner if signs of recurrent ischaemia developed. SETTING--University department of cardiology. PATIENTS--196 consecutive patients undergoing coronary angioplasty from the beginning of April 1987 to the end of March 1989 and meeting the selection criteria that included the presence of at least one of six predefined risk factors for restenosis. At the time of coronary angioplasty 113 patients had unstable angina or non-Q wave infarction and 83 had stable angina pectoris. RESULTS--In 89 (91%) patients in the verapamil group and in 83 (85%) control patients follow up angiograms were available. The restenosis rate was lower in the verapamil group (48.3%) than in the placebo group (62.7%) (odds ratio 0.56, 95% confidence interval (CI) 0.303 to 1.025 p = 0.059). Of the 172 patients in whom follow up angiograms were available, 24 (13 taking verapamil and 11 taking placebo) did not comply with the trial for more than 40 (34) days (mean (1 SD)). For the remaining 148 patients the restenosis rate was 47.4% in the verapamil group and 63.9% in the placebo group (odds ratio 0.52, 95% CI 0.271 to 0.993, p = 0.046). In the 97 patients with unstable angina or non-Q wave infarction the restenosis rate was not significantly influenced by verapamil (55.8% with verapamil v 62.2% with placebo, odds ratio 0.77, 95% CI 0.339 to 1.728, p = 0.520). In the 75 patients with stable angina pectoris the restenosis rate dropped from 63.2% with placebo to 37.8% with verapamil (odds ratio 0.36, 95% CI 0.137 to 0.917, p = 0.038). CONCLUSION--The observed beneficial effect of high-dose verapamil treatment on the angiographic restenosis rate in patients with stable angina pectoris and at increased risk of recurrent obstruction requires confirmation in further prospective studies.     

Minimum effective intensity of oral anticoagulant therapy in primary prevention of coronary heart disease

BACKGROUND: There is mounting evidence that low-intensity oral anticoagulation is effective, particularly in primary prevention of thrombosis, with important implications for safety and the practicalities of using warfarin. Because it is desirable to know possible benefits for different indications so that optimal therapy can be administered in as wide a range of conditions as possible, we analyzed data from the Thrombosis Prevention Trial, a factorial trial that compared treatment with low-intensity, dose-adjusted warfarin and low-dose aspirin separately and together, to determine the minimum effective intensity of oral anticoagulation in the primary prevention of coronary heart disease. METHODS: The international normalized ratio (INR) most recent to an event and overall time at each INR were used to calculate the INR-related event rate for coronary events, strokes, and major and minor bleeding episodes in 2545 men receiving warfarin with or without aspirin (75 mg/d) and followed up for a total of 9952 person-years. RESULTS: Compared with placebo, warfarin alone at a dose that maintained the INR at 1.4 or more significantly reduced the risk of a coronary event by 47% (95% confidence interval, 4%-70%; P =.03), whereas the risk of a coronary event was not reduced at INRs below 1. 4. Coronary events, strokes, and major bleeding episodes combined were significantly reduced by 45% (95% confidence interval, 9%-67%; P =.02) in the warfarin group compared with the placebo group when the INR was 1.4 or more. Minor bleeding episodes increased as the INR rose above about 2.0. No significant association of INR with coronary events was observed with combined warfarin and aspirin, possibly reflecting the small number of such events that occurred in this group, therefore limiting the power to detect an association with INR. CONCLUSIONS: Warfarin alone is effective in the primary prevention of coronary heart disease when the dose is adjusted to maintain an INR of 1.4 or more. The results add to the evidence that low-intensity, dose-adjusted oral anticoagulation is effective for a range of conditions.     

华法令和肠溶阿司匹林防治高龄不稳定型心绞痛的疗效对比

目的探讨华法令和肠溶阿司匹林用于预防不稳定型心绞痛患者发生急性心肌梗死和心脏性死亡的疗效。方法应用统一人群分组对照群组研究的方法,在本院住院和门诊的高龄患者中随机挑选服用阿司匹林(ASA300mg/d)者73例,服用华法令(WFR2～5mg/d)者82例,并随访12个月。结果用药14d后,WFR组患者心绞痛改善率明显高于ASA组(86.6%vs67.1%),P<0.01。随访12个月期间,复合终点事件(非致死性急性心肌梗死和心脏性死亡)WFR组明显低于ASA组(9.8%vs26.0%),P<0.01。结论华法令防治不稳定型心绞痛的近期和远期疗效显著,优于阿司匹林组,小剂量应用副作用小,值得推广。     

Safety and efficacy of combined antiplatelet-warfarin therapy after coronary stenting.

AIM: The aim of this study was to evaluate the antithrombotic treatment adopted after coronary stenting in patients requiring long-term anticoagulation. METHODS AND RESULTS: We analysed retrospectively all consecutive patients on warfarin therapy (n = 239, mean age 70 years, men 74%) who underwent percutaneous coronary intervention (PCI) in 2003-04 in six hospitals. An age- and sex-matched control group with similar disease presentation (unstable or stable symptoms) was selected from the study period. Primary endpoint was defined as the occurrence of death, myocardial infarction, target vessel revascularization, or stent thrombosis at 12 months. Warfarin treatment was an independent predictor of both primary endpoint (OR 1.7, 95% CI 1.0-3.0, P = 0.05) and major bleeding (OR 3.4, 95% CI 1.2-9.3, P = 0.02). Triple therapy with aspirin and clopidogrel was the most common (48%) option in stented patients in warfarin group, and there was a significant (P = 0.004) difference between the drug combinations in stent thrombosis with the highest (15.2%) incidence in patients receiving warfarin plus aspirin combination. CONCLUSION: Our study shows that the prognosis is unsatisfactory in warfarin-treated patients irrespective of the drug combination used. Aspirin plus warfarin combination seems to be inadequate to prevent stent thrombosis.     

Echocardiographic determination of left atrial function and its application for assessment of mitral flow velocity pattern

Forty-three patients presenting with unstable angina or myocardial infarction were randomised double blind to warfarin [target international normalised ratio (INR), 2.0 to 2.5] and aspirin (150 mg) daily or placebo plus aspirin (150 mg) daily. Coronary flow was assessed with the thrombolysis in myocardial infarction (TIMI) flow grade and corrected TIMI frame count (CTFC). Coronary artery flow was reduced (higher CTFC) at baseline in culprit arteries (mean +/-SD, 37.1+/-15.4 frames) compared to nonculprit arteries (22.5+/-6.7 frames, P<0.0001). In patients with a patent artery at follow-up, coronary flow was unchanged after ten weeks of warfarin and aspirin (-2.0+/-19.9 frames) or aspirin alone (3.8+/-10.4 frames, P = 0.20). Patients randomised to aspirin alone were more likely to progress to total occlusion [aspirin, 7 of 19 (37%) vs. warfarin and aspirin, 1 of 24 (4%); P = 0.01). Higher baseline culprit artery CTFC was also associated with an increased risk of late occlusion [+10 frames; odds ratio (OR), 1.65; 95% CI, 1.01 to 2.33]. Coronary flow remained impaired ten weeks after presentation with myocardial infarction or unstable angina. Combination warfarin and aspirin therapy did not improve flow in vessels that remained patent but did reduce the risk of progression to occlusion.     

The effect of fluvastatin on cardiac events in patients with symptomatic coronary artery disease during one year of treatment.

The primary objective of the present study was to investigate the cholesterol-lowering effect of fluvastatin on the incidence of cardiac events in hyperlipidaemic patients with symptomatic, clinically-diagnosed (exercise-ECG) coronary heart disease (CHD) during 1 year of treatment. Exercise tolerance, incidence of angina pectoris episodes, use of anti-anginal medication and intimal-medial-thickness (IMT subgroup) of the A. carotis were secondary endpoints. In the double-blind trial a total of 365 male and female patients with stable symptomatic CHD and a low-density lipoprotein cholesterol (LDL-C) above 160 mg/dl on a lipid-lowering diet were randomised to fluvastatin 40 mg (o.a.d. or b.i.d.) or placebo for 1 year. Fluvastatin lowered total cholesterol by 17% and LDL-C by 27%. There was a significantly lower incidence of cardiac events (cardiac death, nonfatal myocardial infarction, unstable angina pectoris) in the fluvastatin group (3 events) as compared to the placebo group (10 events) (P < 0.05). Exercise tolerance improved and the incidence of angina pectoris episodes decreased in both groups, but more pronounced on fluvastatin (n.s.). Exercise-ECG discontinuation due to angina pectoris and ST-segment depression decreased in the fluvastatin group by 55.6 and 70.9%, respectively, and in the placebo group by 39.6 and 46.5% (n.s.). At baseline, a subgroup of 76 patients showed a mean IMT value of 0.73 mm which remained uninfluenced in the fluvastatin and the placebo groups. Fluvastatin was safe and well tolerated. In conclusion, patients with symptomatic CHD get cardiovascular benefit from lipid-lowering therapy with fluvastatin even during the first year of treatment.     

Increased unrecognized coronary heart disease and sudden deaths in rheumatoid arthritis: a population-based cohort study

OBJECTIVE: To examine the risk of clinical coronary heart disease (CHD) in patients with rheumatoid arthritis (RA) compared with age- and sex-matched non-RA subjects, and to determine whether RA is a risk factor for CHD after accounting for traditional CHD risk factors. METHODS: We assembled a population-based incidence cohort of 603 Rochester, Minnesota residents ages >or=18 years who first fulfilled the American College of Rheumatology (ACR) 1987 criteria for RA between January 1, 1955 and January 1, 1995, and 603 age- and sex-matched non-RA subjects. All subjects were followed up through their complete inpatient and outpatient medical records, beginning at age 18 years until death, migration, or January 1, 2001. Data were collected on CHD events and traditional CHD risk factors (diabetes mellitus, hypertension, dyslipidemia, body mass index, smoking) using established diagnostic criteria. CHD events included hospitalized myocardial infarction (MI), unrecognized MI, coronary revascularization procedures, angina pectoris, and sudden CHD deaths. Conditional logistic regression and Cox regression models were used to estimate the risk of CHD associated with RA, both prior to and following RA diagnosis, after adjusting for CHD risk factors. RESULTS: During the 2-year period immediately prior to fulfillment of the ACR criteria, RA patients were significantly more likely to have been hospitalized for acute MI (odds ratio [OR] 3.17, 95% confidence interval [95% CI] 1.16-8.68) or to have experienced unrecognized MIs (OR 5.86, 95% CI 1.29-26.64), and less likely to have a history of angina pectoris (OR 0.58, 95% CI 0.34-0.99) compared with non-RA subjects. After the RA incidence date, RA patients were twice as likely to experience unrecognized MIs (hazard ratio [HR] 2.13, 95% CI 1.13-4.03) and sudden deaths (HR 1.94, 95% CI 1.06-3.55) and less likely to undergo coronary artery bypass grafting (HR 0.36, 95% CI 0.16-0.80) compared with non-RA subjects. Adjustment for the CHD risk factors did not substantially change the risk estimates. CONCLUSION: Patients with RA have a significantly higher risk of CHD when compared with non-RA subjects. RA patients are less likely to report symptoms of angina and more likely to experience unrecognized MI and sudden cardiac death. The risk of CHD in RA patients precedes the ACR criteria-based diagnosis of RA, and the risk cannot be explained by an increased incidence of traditional CHD risk factors in RA patients.     

Increased unrecognized coronary heart disease and sudden deaths in rheumatoid arthritis: A population‐based cohort study

Objective

To examine the risk of clinical coronary heart disease (CHD) in patients with rheumatoid arthritis (RA) compared with age‐ and sex‐matched non‐RA subjects, and to determine whether RA is a risk factor for CHD after accounting for traditional CHD risk factors.

Methods

We assembled a population‐based incidence cohort of 603 Rochester, Minnesota residents ages ≥18 years who first fulfilled the American College of Rheumatology (ACR) 1987 criteria for RA between January 1, 1955 and January 1, 1995, and 603 age‐ and sex‐matched non‐RA subjects. All subjects were followed up through their complete inpatient and outpatient medical records, beginning at age 18 years until death, migration, or January 1, 2001. Data were collected on CHD events and traditional CHD risk factors (diabetes mellitus, hypertension, dyslipidemia, body mass index, smoking) using established diagnostic criteria. CHD events included hospitalized myocardial infarction (MI), unrecognized MI, coronary revascularization procedures, angina pectoris, and sudden CHD deaths. Conditional logistic regression and Cox regression models were used to estimate the risk of CHD associated with RA, both prior to and following RA diagnosis, after adjusting for CHD risk factors.

Results

During the 2‐year period immediately prior to fulfillment of the ACR criteria, RA patients were significantly more likely to have been hospitalized for acute MI (odds ratio [OR] 3.17, 95% confidence interval [95% CI] 1.16–8.68) or to have experienced unrecognized MIs (OR 5.86, 95% CI 1.29–26.64), and less likely to have a history of angina pectoris (OR 0.58, 95% CI 0.34–0.99) compared with non‐RA subjects. After the RA incidence date, RA patients were twice as likely to experience unrecognized MIs (hazard ratio [HR] 2.13, 95% CI 1.13–4.03) and sudden deaths (HR 1.94, 95% CI 1.06–3.55) and less likely to undergo coronary artery bypass grafting (HR 0.36, 95% CI 0.16–0.80) compared with non‐RA subjects. Adjustment for the CHD risk factors did not substantially change the risk estimates.

Conclusion

Patients with RA have a significantly higher risk of CHD when compared with non‐RA subjects. RA patients are less likely to report symptoms of angina and more likely to experience unrecognized MI and sudden cardiac death. The risk of CHD in RA patients precedes the ACR criteria–based diagnosis of RA, and the risk cannot be explained by an increased incidence of traditional CHD risk factors in RA patients.

     

The Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial programme; rationale, design and baseline characteristics including a meta-analysis of the effects of thienopyridines in vascular disease.

BACKGROUND: Other than aspirin, there are few oral antithrombotic treatments with proven efficacy in patients with acute coronary syndrome. In this report, we present the rationale, design and baseline characteristics of the Clopidogrel in Unstable angina to prevent Recurrent ischaemic Events (CURE) trial, which includes a meta-analysis of the effects of thienopyridines in patients with vascular disease. METHODS AND RESULTS: Combined data from randomized trials of thienopyrindines in patients with atherosclerotic disease demonstrated a 29% reduction in vascular events when compared with placebo/control (n=2392) (OR 0.71, 95% CI 0.58-0.86, P=0.0006) and a 10% reduction in vascular events when compared with aspirin (n=22 254) (OR 0.91, 95% Cl 0.84-0.99, P=0.039). Similarly, randomized trials of aspirin plus thienopyridines in patients undergoing intracoronary stenting, demonstrated a marked benefit of aspirin plus ticlopidine in reducing death or myocardial infarction compared with aspirin alone (OR 0.23, 95% CI 0.11-0.49, P=0.0001) or aspirin plus warfarin (OR 0.51, 95% CI 0.33-0.78, P=0.002). Whether these benefits extend to the much larger population of patients with acute coronary syndrome is unknown. CURE is an international, randomized, double-blind trial, in which patients with acute coronary syndrome will be randomized to receive either a bolus dose of clopidogrel (300 mg) followed by 75 mg per day for 3-12 months, or matching placebo. Both groups will receive aspirin. The co-primary efficacy end-points of CURE are: (1) the composite of cardiovascular death, myocardial infarction or stroke; and (2) the composite of cardiovascular death, myocardial infarction, stroke or refractory ischaemia. CURE will recruit approximately 12 500 patients with acute coronary syndrome (from 28 countries) and its power to detect moderate treatment benefits will be in the region of 80-90%, while maintaining an overall type I error (alpha) of 0.05. The baseline characteristics of the study population are consistent with at least a moderate risk group of patients with acute coronary syndrome. CONCLUSIONS: Randomized trials of thienopyridines in patients with vascular disease demonstrate that thienopyridines are effective in reducing vascular events when compared with placebo/control or aspirin, as well as when used in combination with aspirin in patients undergoing intracoronary stent implantation. The CURE trial is a large international study to determine if acute and long-term treatment with the combination of clopidogrel and aspirin is superior to aspirin alone in patients with acute coronary syndrome.     

华法令对经皮冠状动脉介入治疗术后心肌缺血的疗效观察

为观察华法令对经皮冠状动脉介入治疗术后心绞痛与无症状性心肌缺血的疗效。将我院经皮冠状动脉介入治疗术后有心绞痛或无症状性心肌缺血的86例患者,随机分为两组,对照组按常规治疗,治疗组除常规治疗外加华法令,对比观察两组心绞痛缓解与消失时间,无症状性心肌缺血发作次数及心肌缺血总负荷的改变,并观察华法令的副作用。结果发现,治疗组和对照组的心绞痛缓解时间分别为3.28±1.67 d和4.98±1.69 d(p<0.01);消失时间分别为8.87±0.60 d和11.04±3.68 d(p<0.01);有效率分别为90.0%和73.9%(p<0.05)。心肌缺血总负荷差值分别为659.1±257.6 mms和369.7±297.2 mms(p<0.01)。说明治疗组心绞痛与无症状性心肌缺血改善比对照组明显,极少数患者虽出现出血副作用,但不严重。此结果提示,华法令对经皮冠状动脉介入治疗术后心绞痛与无症状性心肌缺血有一定疗效,可作为重要辅助治疗,只要严格按用药要求是安全的。     

Warfarin and aspirin did not differ for death or stroke in heart failure and sinus rhythm

QUESTION What are the relative efficacy and safety of warfarin and aspirin in patients with heart failure who are in sinus rhythm? METHODS DESIGN Randomized controlled trial (Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction [WARCEF] trial). ClinicalTrials.gov NCT00041938. ALLOCATION {Concealed}*.? BLINDING Blinded? (patients, clinicians, {data collectors, safety committee}*, and outcome assessors). FOLLOW-UP PERIOD ≤?6 years (mean 3.5 y). SETTING 168 centers in the USA, Canada, Argentina, and Europe. PATIENTS 2305 adults ≥?18 years of age (mean age 61 y, 80% men) who had a left ventricular ejection fraction (LVEF) ≤?35% and normal sinus rhythm, and planned treatment with a β-blocker, angiotensin-converting enzyme inhibitor, or hydralazine and nitrates. Exclusion criteria included modified Rankin score >?4, medical conditions with high risk for cardiac embolism, clear indication for warfarin or aspirin, or contraindication to warfarin. Patients in New York Heart Association class I were eligible but could not comprise >?20% of randomized patients. INTERVENTION Active warfarin (with target international normalized ratio 2.0 to 3.5) plus aspirin placebo (n =?1142), or aspirin, 325 mg/d, plus warfarin placebo (n =?1163). OUTCOMES Primary composite endpoint of ischemic stroke, intracerebral hemorrhage (ICH), or death. Secondary outcome was a composite of ischemic stroke, ICH, death, myocardial infarction, or hospitalization for heart failure. The safety outcome was a composite of ischemic stroke, ICH, death, or intracranial hemorrhage. The trial had 69% power to detect a relative hazard reduction of 17.8% in the primary outcome and 83% power for the secondary outcome. PATIENT FOLLOW-UP {93%}* (96% for vital status; intention-to-treat analysis). MAIN RESULTS Enrolment was stopped early because of slow recruitment. Groups did not differ for the primary composite outcome or any of its components except for ischemic stroke (Table). Groups also did not differ for the secondary or safety composite endpoints (Table). CONCLUSION In patients with heart failure who are in sinus rhythm, warfarin and aspirin did not differ for a composite of death or ischemic or hemorrhage outcomes.Warfarin vs aspirin in patients with heart failure who are in sinus rhythm?OutcomesEvents / 100 patient-yAt a mean 3.5 yWarfarinAspirinRRR (95% CI)NNT (CI)Primary composite§7.57.9{4% (-10 to 16)}||Not significantSafety composite?7.68.0{3% (-11 to 15)}||Not significantRRI (CI)NNH (CI)Secondary composite**12.712.2{5% (-6 to 16)}||Not significant?Abbreviations defined in Glossary.§Ischemic stroke {0.7 vs 1.4, RRR 46%, 95% CI 16 to 65}||, intracerebral hemorrhage {0.12 vs 0.05, RRI 155%, CI -51 to 1210}||, or death {6.6 vs 6.5, RRI 4%, CI -11 to 20}||.||Estimates provided by author.?Ischemic stroke, intracerebral hemorrhage, death, or intracranial hemorrhage.**Ischemic stroke, intracerebral hemorrhage, death, myocardial infarction, or hospitalization for heart failure.     

Low-dose aspirin therapy for chronic stable angina. A randomized, placebo-controlled clinical trial

OBJECTIVE: To evaluate the efficacy of low-dose aspirin in the primary prevention of myocardial infarction among patients with chronic stable angina. DESIGN: A randomized, double-blind, trial. PATIENTS: The study included 333 men with baseline chronic stable angina but with no previous history of myocardial infarction, stroke, or transient ischemic attack who were enrolled in the Physicians' Health Study, a trial of aspirin among 22,071 male physicians. INTERVENTION: Patients were randomly assigned to receive alternate-day aspirin therapy (325 mg) or placebo and were followed for an average of 60.2 months for the occurrence of myocardial infarction, stroke, or cardiovascular death. RESULTS: During follow-up, 27 patients had confirmed myocardial infarctions; 7 were among the 178 patients with chronic stable angina who received aspirin therapy and 20 were among the 155 patients who received placebo (relative risk, 0.30; 95% CI, 0.14 to 0.63; P = 0.003). While simultaneously controlling for other cardiovascular risk factors in a proportional hazards model, an overall 87% risk reduction was calculated (relative risk, 0.13; CI, 0.04 to 0.42; P less than 0.001). For the subgroup of patients with chronic stable angina but no previous coronary bypass surgery or coronary angioplasty, an almost identical reduction in the risk for myocardial infarction was found (relative risk, 0.14; CI, 0.04 to 0.56; P = 0.006). Of 13 strokes, 11 occurred in the aspirin group and 2 in the placebo group (relative risk, 5.4; CI, 1.3 to 22.1; P = 0.02). No stroke was fatal, but 4 produced some long-term impairment of function. One stroke, in the aspirin group, was hemorrhagic. CONCLUSION: Our data indicated that alternate-day aspirin therapy greatly reduced the risk for first myocardial infarction among patients with chronic stable angina, a group of patients at high risk for cardiovascular death (P less than 0.001). Although our results for stroke were based on small numbers, they suggested an apparent increase in frequency of stroke with aspirin therapy; this finding requires confirmation in randomized trials of adequate sample size.     

Prevention of thromboembolism in atrial fibrillation

OBJECTIVE: Appropriate use of drugs to prevent thromboembolism in patients with atrial fibrillation (AF) involves comparing the patient's risk of stroke and risk of hemorrhage. This review summarizes the evidence regarding the efficacy of these medications. METHODS: We conducted a meta-analysis of randomized controlled trials of drugs used to prevent thromboembolism in adults with nonpostoperative AF. Articles were identified through the Cochrane Collaboration's CENTRAL database and MEDLINE until May 1998. MAIN RESULTS: Eleven articles met criteria for inclusion in this review. Warfarin was more efficacious than placebo for primary stroke prevention (aggregate odds ratio [OR] of stroke = 0.30, 95% confidence interval [CI] 0.19, 0.48), with moderate evidence of more major bleeding (OR 1.90; 95% CI 0.89, 4.04). Aspirin was inconclusively more efficacious than placebo for stroke prevention (OR 0.56, 95% CI 0.19, 1.65), with inconclusive evidence regarding more major bleeds (OR 0.81, 95% CI 0.37, 1.77). For primary prevention, assuming a baseline risk of 45 strokes per 1,000 patient-years, warfarin could prevent 30 strokes at the expense of only 6 additional major bleeds. Aspirin could prevent 17 strokes, without increasing major hemorrhage. In direct comparison, there was evidence suggesting fewer strokes among patients on warfarin than among patients on aspirin (aggregate OR 0.64, 95% CI 0.43, 0.96), with only suggestive evidence for more major hemorrhage (OR 1.60, 95% CI 0.77,3.35). However, in younger patients, with a mean age of 65 years, the absolute reduction in stroke rate with warfarin compared with aspirin was low (5.5 per 1,000 person-years) compared with an older group (15 per 1,000 person-years). CONCLUSION: In general, the evidence strongly supports warfarin for patients with AF at average or greater risk of stroke. Aspirin may prove to be useful in subgroups with a low risk of stroke, although this is not definitively supported by the evidence.     

Heart Disease Risk Factors in Midlife Predict Subclinical Coronary Atherosclerosis More than 25 Years Later in Survivors without Clinical Heart Disease: The Rancho Bernardo Study

OBJECTIVES: To determine which of the classic modifiable coronary heart disease (CHD) risk factors, measured in midlife, are associated with subclinical coronary atherosclerosis in older age.
DESIGN: Prospective study.
SETTING: Community based.
PARTICIPANTS: Participants were 400 community-dwelling middle-aged adults who had no history of CHD at baseline (1972–1974), when CHD risk factors were measured, and who were still free of known CHD in 2000 to 2002.
MEASUREMENTS: Coronary artery plaque burden was assessed according to coronary artery calcium (CAC) score using computed tomography in 2000 to 2002.
RESULTS: Ordinal logistic regression analysis was used to compare baseline risk factors with severity of CAC. Mean age was 42 at baseline and 69 at the time of CAC assessment; 46.5% were male. In analyses adjusted for age, sex, and all other risk factors, one standard deviation increase in body mass index (odds ratio (OR)=1.24, 95% confidence interval (CI)=1.02–1.51; P =.03), cholesterol (OR=1.28, 95% CI=1.03–1.58; P =.020, pulse pressure (OR=1.24, 95% CI=1.03–1.50; P =.03), and log triglycerides (OR=1.22, 95% CI=0.99–1.50; P =.06) each independently predicted the presence and severity of coronary artery atherosclerosis.
CONCLUSION: Modifiable risk factors measured more than 25 years earlier influence plaque burden in elderly survivors without clinical heart disease.     

Residual high-grade angina after enhanced external counterpulsation therapy

OBJECTIVE: We evaluated the degree of residual angina on the outcomes of enhanced external counterpulsation (EECP) therapy for chronic stable angina. BACKGROUND: Angina refractory to medical therapy is common in the pool of patients who are not completely revascularized by angioplasty or bypass surgery. METHODS: We examined 902 patients enrolled from 1998 to 2001 in the Second International Enhanced External Counterpulsation Patient Registry. Baseline and outcome variables were stratified by the last recorded Canadian Cardiovascular Society class. RESULTS: Residual Class 3 (12.1%) or 4 (2.3%) angina was uncommon among patients with severe coronary artery disease after treatment with EECP. Prevalence of diabetes, hypertension, dyslipidemia, and heart failure was similar among the anginal post-EECP anginal classes. Multivessel coronary disease was more common in those with higher-grade angina at completion. More frequent and severe angina at entry was more common in those with the higher anginal classes at EECP (P<.001). There were no differences in the rates of chronic medications utilized or prior revascularization. At 3-year follow-up, rates of death, myocardial infarction, percutaneous coronary intervention, and coronary artery bypass surgery tended to be higher across increasing residual angina classes. The composite cardiac event rates were 34%, 33%, and 44% for those with Class 0, Class 1/2, and Class 3/4 angina at EECP completion (P=.01), respectively. Multivariate analysis for the composite endpoint found residual Class 3/4 angina (OR=1.59, 95% CI=1.19-2.17, P=.002), diabetes (OR=1.57, 95% CI=1.23-2.01, P=.0003), age (per decile OR=1.17, 95% CI=1.04-1.31, P=.007), and greater EECP augmentation (OR=0.79, 95% CI=0.65-0.96, P=.02) as significant predictors. CONCLUSIONS: Residual high-grade angina after EECP occurs in those with more severe angina and multivessel disease at baseline and is associated with cardiac events over the next 3 years. These data suggest that close clinical observation and intensive management of those with high-grade angina post-EECP are warranted.     

Outcomes in the management of atrial fibrillation: clinical trial results can apply in practice

Background: The benefits of antithrombotic therapy in chronic atrial fibrillation (AF) have been established in clinical trials, but there is a paucity of data on outcomes in practice. Aims: The objective was to establish a large ongoing database of patients with non‐valvular AF, to enable the accurate determination of clinical outcomes. Methods: A retrospective review of the medical records for consecutive patients who had AF documented on electrocardiogram at the major teaching hospital in Tasmania between 1 January 1997 and 30 June 1999 was performed. An extensive range of demographic and clinical variables was recorded for all patients with chronic or paroxysmal non‐valvular AF. Results: The 505 patients (60% males) included in the database had a median age of 76 years. According to risk stratification criteria, 79% of the patients with previously diagnosed chronic or paroxysmal AF had a high risk of developing stroke at the time of admission to hospital care. However, only one‐third (34%) of these patients were receiving warfarin (or warfarin plus aspirin), with almost one‐quarter (24%) receiving no antithrombotic agent. The annual incidence of ischaemic strokes was 3.4% (1.5–6.4%; 95% CI) when taking warfarin, compared to 7.0% (5.2–9.4%) for patients not taking warfarin and 7.8% (5.4–11.1%) for patients taking aspirin. The annual incidence of bleeding complications in patients taking warfarin was 14.2% (10.0–19.5%) overall and 3.4% (1.5–6.4%) for major bleeds. In patients not taking warfarin, the overall annual incidence of bleeds was 8.4% (6.3–10.9%) and 3.9% (2.5–5.7%) for major bleeds. Conclusions: Warfarin is underused in patients with AF. In clinical practice, warfarin confers a similar stroke risk reduction to that observed in trials, with an increase in incidence of only minor bleeding complications. Aspirin did not appear to reduce the risk of stroke. (Intern Med J 2001; 31: 329–336)     

Usefulness of antithrombotic therapy in resting angina pectoris or non-Q-wave myocardial infarction in preventing death and myocardial infarction (a pilot study from the Antithrombotic Therapy in Acute Coronary Syndromes Study Group)

In a prospective pilot trial of antithrombotic therapy in the acute coronary syndromes (ATACS) of resting and unstable angina pectoris or non-Q-wave myocardial infarction, 3 different antithrombotic regimens in the prevention of recurrent ischemic events were compared for efficacy. Ninety-three patients were randomized to receive aspirin (325 mg/day), or full-dose heparin followed by warfarin, or the combination of aspirin (80 mg/day) plus heparin and then warfarin. Trial antithrombotic therapy was added to standardized antianginal medication and continued for 3 months or until an end point was reached. Analysis, by intention-to-treat, of the 3-month end points, revealed the following: recurrent ischemia occurred in 7 patients (22%) after aspirin, in 6 patients (25%) after heparin and warfarin, and in 16 patients (43%) after aspirin combined with heparin and then warfarin; coronary revascularization occurred in 12 patients (38%) after aspirin, in 12 patients (50%) after heparin and warfarin, and in 22 patients (60%) after aspirin combined with heparin and then warfarin; myocardial infarction occurred in 1 patient (3%) after aspirin, in 3 patients (13%) after heparin and warfarin, and in no patient after aspirin combined with heparin and then warfarin; no deaths occurred after aspirin or after aspirin combined with heparin and then warfarin, but 1 patient (4%) died after warfarin alone; major bleeding occurred in 3 patients (9%) after aspirin, in 2 patients (8%) after heparin and warfarin, and in 3 patients (8%) after aspirin combined with heparin and then warfarin. Recurrent myocardial ischemia occurred at 3 +/- 3 days after randomization.(ABSTRACT TRUNCATED AT 250 WORDS)     

Progression of the Culprit Lesion in Unstable Coronary Artery Disease With Warfarin and Aspirin Versus Aspirin Alone: Preliminary Study

Objectives. This study assessed whether combination therapy with aspirin and warfarin for 10 weeks reduces the risk of progression or reocclusion of the unstable coronary artery lesion.Background. Reocclusion of the culprit coronary artery occurs in up to one third of patients during the 3 months after myocardial infarction (MI) or unstable angina and is associated with increased morbidity and mortality.Methods. Fifty-seven patients presenting with unstable angina or MI who had an identifiable culprit lesion at coronary angiography were randomized in double-blind manner to receive warfarin (target international normalized ratio [INR] 2.0 to 2.5) or placebo in addition to aspirin (150 mg daily). Changes in the culprit lesion were assessed by quantitative angiography in 50 patients after 10 weeks of therapy or after a clinical event. Progression of the culprit lesion was defined as a decrease in minimal lumen diameter >0.4 mm or a new total occlusion. Regression was defined as an increase in minimal lumen diameter >0.4 mm.Results. In subjects randomized to receive warfarin, the culprit lesion was less likely to progress (1 [4%] vs. 8 [33%]) and more likely to regress (5[19%] vs. 2[9%]) than in subjects receiving placebo (p = 0.02). Recurrent MI or a new occlusion at angiography occurred in 2 (7%) of 29 patients receiving warfarin versus 11 (39%) of 28 patients receiving placebo (p = 0.005).Conclusions. In patients with an acute coronary syndrome, combined therapy with aspirin and warfarin with a target INR of 2.0 to 2.5 for 10 weeks reduces the risk of progression or reocclusion of the culprit coronary lesion.