Syed M. Jafri

Randomized Trial of Warfarin, Aspirin, and Clopidogrel in Patients With Chronic Heart Failure: The Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) Trial

Background— Chronic heart failure remains a major cause of mortality and morbidity. The role of antithrombotic therapy in patients with chronic heart failure has long been debated. The objective of this study was to determine the optimal antithrombotic agent for heart failure patients with reduced ejection fractions who are in sinus rhythm. Methods and Results— This prospective, randomized clinical trial of open-label warfarin (target international normalized ratio of 2.5 to 3.0) and double-blind treatment with either aspirin (162 mg once daily) or clopidogrel (75 mg once daily) had a 30-month enrollment period and a minimum of 12 months of treatment. We enrolled 1587 men and women ≥18 years of age with symptomatic heart failure for at least 3 months who were in sinus rhythm and had left ventricular ejection fraction of ≤35%. The primary outcome was the time to first occurrence of death, nonfatal myocardial infarction, or nonfatal stroke. For the primary composite end point, the hazard ratios were as follows: for warfarin versus aspirin, 0.98 (95% CI, 0.86 to 1.12; P=0.77); for clopidogrel versus aspirin, 1.08 (95% CI, 0.83 to 1.40; P=0.57); and for warfarin versus clopidogrel, 0.89 (95% CI, 0.68 to 1.16; P=0.39). Warfarin was associated with fewer nonfatal strokes than aspirin or clopidogrel. Hospitalization for worsening heart failure occurred in 116 (22.2%), 97 (18.5%), and 89 (16.5%) patients treated with aspirin, clopidogrel, and warfarin, respectively (P=0.02 for warfarin versus aspirin). Conclusion— The primary outcome measure and the mortality data do not support the primary hypotheses that warfarin is superior to aspirin and that clopidogrel is superior to aspirin.

Fecal Microbiota Transplantation is Safe and Efficacious for Recurrent or Refractory Clostridium difficile Infection in Patients with Inflammatory Bowel Disease

Background:New treatments are needed as Clostridium difficile infection (CDI) is becoming increasingly formidable. Fecal microbiota transplantation (FMT) has a 90% success rate in the treatment of recurrent CDI. However, evidence regarding its safety, efficacy, and effect on disease activity in patients with inflammatory bowel disease (IBD) is lacking. Methods:This cohort study used data from 8 national and international academic centers. Patients with established IBD who underwent FMT for recurrent CDI were followed for a minimum of 3 months. The primary outcome was CDI recurrence at 3 months after FMT. The secondary outcomes were (1) IBD activity and severity at 3 months based on the judgment of the treating physician, endoscopic findings, and clinical disease activity scores; and (2) safety. Results:Sixty-seven patients were included in the analysis. Thirty-five (52%) had Crohns disease, 31 (46%) ulcerative colitis, and one indeterminate colitis with 43 (64%) patients on an immunosuppressive agent at the time of FMT. The initial FMT was successful in 53 (79%) patients. After the FMT, IBD disease activity was reported as improved in 25 (37%), no change in 20 (30%), and worse in 9 (13%) patients. Serious adverse events included colectomy (1.4%), hospitalization for CDI (2.9%), hospitalization for IBD flare (2.9%), small bowel obstruction (1.4%), CMV colitis (1.4%), and pancreatitis (1.4%). Discussion:The overall CDI cure rates were high, with a large percentage of patients experiencing clinical improvement of their IBD after FMT. A minority of patients developed an IBD flare. No severe adverse events directly attributable to FMT were found in this largest reported series of recurrent or refractory CDI patients with concurrent IBD.

Effects of warfarin on markers of hypercoagulability in patients with heart failure

Heart failure is associated with a hypercoagulable state. A single-center, randomized, double-blind, placebo-controlled trial was performed to test the hypothesis that warfarin will modify a hypercoagulable state in heart failure. This study included 76 patients with heart failure. At baseline, patients had evidence for a hypercoagulable state with elevated plasma levels of thrombin/antithrombin III (TAT) complexes (3.4 +/- 2.0 ng/ml), prothrombin fragment F1 + 2 (1.5 +/- 0.9 nmol/L), and D-dimers (630 +/- 401 ng/ml). Warfarin therapy (international normalized ratio [INR] 2.7 +/- 1.3) significantly decreased plasma levels of TAT complexes (p < 0.002), F1 + 2 (p < 0.001), and D-dimers (p < 0.001) when compared with baseline values at 1, 2, and 3 months of therapy. In contrast, patients receiving placebo had persistent elevation of TAT complexes (p = not significant [NS]), F1 + 2 (p = NS), and D-dimers (p = NS) during follow-up at 1, 2, and 3 months. The two treatment groups followed different trends over time for all three markers (p < 0.001). The effect of low-intensity warfarin (INR 1.3 +/- 0.08) versus moderate-intensity warfarin (INR 2.3 +/- 1.1 ) on markers of hypercoagulability was evaluated in 14 patients. When compared with baseline, low-intensity warfarin administration decreased plasma levels of TAT complexes (p = NS), F1 + 2 (p = 0.05), and D-dimers (p = 0.04). In these patients F1 + 2 was further reduced with moderate-intensity warfarin (p < 0.001). Our findings suggest that a hypercoagulable state in heart failure can be modified by warfarin therapy.

Antithrombotic therapy in atrial fibrillation: A review of randomized trials with special reference to the stroke prevention in atrial fibrillation II (SPAF II) trial

Nonvalvular atrial fibrillation is common and is associated with a high risk of system embolism. Recently, several large randomized trials have been completed that have established the efficacy of antithrombotic therapy for both primary and secondary prevention of systemic thromboembolism with an acceptable rate of bleeding complications in these patients. This section of clinical trials review summarizes data from all published randomized trials of antithrombotic therapy in atrial fibrillation. The efficacy of aspirin versus warfarin is analyzed. The role of clinical and echo-cardiographic findings to stratify patients is also highlighted. The Stroke Prevention in Atrial Fibrillation II trial is discussed in detail.

Activation of the coagulation system in women with mitral stenosis and sinus rhythm

Abstract Systemic embolism is a frequent complication in mitral stenosis (MS). 1 Its incidence increases with age and the presence of atrial fibrillation. 2,3 Although patients with MS and sinus rhythm can also develop systemic emboli, the frequency of this event is lower in these patients than in those with atrial fibrillation. 1 Patients with MS and atrial fibrillation are considered at high risk of systemic embolism and require anticoagulant therapy. 4 Because patients with MS and sinus rhythm are considered at low risk for systemic embolism, anticoagulant therapy is not routinely recommended. 4 It is desirable to identify patients with MS in sinus rhythm who are at high risk for systemic embolism. There are no reliable clinical or laboratory parameters available to stratify this risk. Recently developed assays are capable of detecting peptides released during activation of the coagulation cascade and thrombogenesis. 5,6 Measurement of these markers may be used to identify patients at risk for thromboembolism. This study was performed to test the hypothesis that there is activation of coagulation in patients with MS and sinus rhythm. Fibrinolytic activity was assayed by measuring D-dimers that are generated from plasmic degradation of cross-linked fibrin. 5 Thrombin activation was assayed by measuring thrombinantithrombin III complexes. 6

Hemodynamic effects of a new type III phosphodiesterase inhibitor (CI-914) for congestive heart failure.

Hemodynamic response after intravenous and oral administration of a new phosphodiesterase inhibitor, CI-914, was studied in 13 patients with severe congestive heart failure. Comparable significant increases in cardiac index of 26% (p less than 0.01) and 19% (p less than 0.02) after intravenous and oral administration were observed. Systemic vascular resistance, right atrial and pulmonary artery wedge pressure decreased significantly after intravenous drug administration. Although similar changes occurred after oral administration, they were not statistically significant. Peak CI-914 plasma concentration occurred 2.3 +/- 2.2 hours after oral drug administration and exhibited measurable hemodynamic effects for up to 10 to 12 hours. Seven of the 13 patients received long-term oral CI-914 for as long as 12 weeks and exhibited an improvement in New York Heart Association functional class and exercise capacity. Five patients died with progressive heart failure, 1 patient died suddenly and 1 died of sepsis. The drug was well tolerated and appears to have potential as a cardiotonic agent.

Effects of cigarette smoking and propranolol in survivors of acute myocardial infarction

The effect of propranolol on mortality and reinfarction after acute myocardial infarction (AMI) in cigarette smokers and nonsmokers was studied in the Beta Blocker Heart Attack Trial. Cigarette smokers (n = 2,332) were 5 years younger than nonsmokers and had a lower incidence of diabetes mellitus, systemic hypertension, previous AMI and cardiomegaly. Among cigarette smokers, the placebo group had a higher total mortality rate than the propranolol group (11.0 vs 7.4%, p less than 0.0008) and more sudden cardiac deaths (7.1 vs 4.6%, p less than 0.009). In nonsmokers the placebo group had a mortality (7.9 vs 7.1%, p greater than 0.64) similar to the propranolol group. After baseline adjustment, cigarette smokers were estimated to have 1.6 times the risk of dying as compared to nonsmokers (p less than 0.0007). Adjusting for baseline differences, both treatment with propranolol and nonsmoking were predictors of survival. No detectable nonsmoking/propranolol interaction could be identified. In survivors of AMI a beneficial effect of propranolol is observed for cigarette smokers. Nevertheless, cigarette smoking continues to be a risk factor for mortality after AMI even for those receiving propranolol.

Antiplatelet and Anticoagulant Therapy in the Prevention of Thromboemboli in Chronic Heart Failure

Thromboembolism is an important complication in patients with heart failure. Several recent clinical trials have established the efficacy of anticoagulant therapy in patients with heart failure and atrial fibrillation. There is renewed interest in examining the role of antiplatelet and anticoagulation therapy in patients with heart failure in sinus rhythm. There is a need to identify patients at risk for thromboembolism in heart failure. However, there are data to suggest that occult thromboembolic events may contribute to disease progression, ischemic events, and sudden cardiac death. This review summarizes the incidence, potential mechanism, and therapeutic approaches for management of thromboembolism in heart failure.

Usefulness of exercise echocardiography in predicting cardiac events in an outpatient population

The prognostic value of exercise echocardiography in an outpatient population is not well defined. A total of 1,020 consecutive patients referred for exercise echocardiography in an ambulatory care setting were studied by reviewing their medical records and exercise echocardiographic data. Of these, 71 (7%) were excluded due to technically inadequate tests, leaving 949 patients who were included in the analysis. A positive exercise echocardiogram (EE) was defined as an appearance of a new wall motion abnormality or worsening of a baseline abnormality. Cardiac events, defined as myocardial infarction, coronary angioplasty, coronary bypass surgery, and death, were documented during a 12-month follow-up period. Cardiac events occurred in 17% of patients (26 of 152) with a positive exercise echocardiogram (EE) and in 2.5% (20 of 797) with a negative EE (p <0.001). The incidence of myocardial infarction (2.6% vs 0.4%, p <0.02), coronary angioplasty (7% vs 1%, p <0.001), and coronary bypass surgery (9% vs 1%, p <0.001) were higher in patients with a positive versus a negative EE. There was 1 death in the positive study group and none in the negative group. Significant independent variables (p <0.05) that predicted cardiac events included a positive exercise electrocardiogram, history of coronary angioplasty, nonspecific ST-T changes on the baseline electrocardiogram, double product <25,000, men, chest pain on exercise test, and a positive exercise electrocardiogram. On a stepwise logistic regression model, exercise echocardiography emerged as an independent predictor of future cardiac events in an outpatient population. This predictive value was enhanced in the presence of a positive exercise electrocardiogram compared with a negative exercise electrocardiogram (24.2% vs 7.9%, p <0.03). Our study suggests that exercise echocardiography is an independent predictor of future cardiac events in an outpatient population.

The role of antiplatelet therapy in acute coronary syndromes and for secondary prevention following a myocardial infarction

Acute Coronary Syndromes: Therapy with aspirin is recommended for all patients with acute myocardial ischemic syndromes unless contraindications for its use is present. None of the studies thus far have conclusively established evidence for a selective dose of aspirin. Until conclusive evidence exists, aspirin in doses of 81 mg (childrens tablet) to 325 mg (adult tablet) are recommended. Ticlopidine may prove to be an attractive alternate choice in those who cannot take aspirin. According to the ACC/AHA task force recommendations, patients with acute myocardial infarction receiving thrombolytic therapy should receive both heparin and aspirin. Aspirin is to be administered in a dose of 160 mg daily. Heparin can be discontinued after 2 days if the patients clinical course remains uncomplicated. Aspirin should be continued indefinitely. An alternative strategy in those who cannot take aspirin is to switch to warfarin before hospital discharge with a view toward long-term anticoagulant therapy. Secondary Prevention: Aspirin in a dose of 325 mg daily is recommended for all survivors of an acute myocardial infarction. No benefit derives from the addition of dipyridamole. The role of sulfinpyrazone remains undefined. Warfarin is an effective antithrombotic alternative to aspirin for secondary prevention after a myocardial infarction. However, aspirin is cheaper to administer and follow up when compared with warfarin. From available information, aspirin appears to be an adequate antithrombotic agent in patients who have near-normal left-ventricular function, the elderly, patients with coexisting cerebrovascular or peripheral vascular disease, and those with contraindications for anticoagulants. Warfarin should be preferred in high-risk patients with anterior or apical myocardial infarction, left-ventricular dysfunction with or without a mural thrombus, and those with associated atrial fibrillation. A randomized study assessing aspirin versus warfarin for secondary prevention after myocardial infarction is being initiated to determine the relative efficacy and safety of these drugs in secondary prevention after myocardial infarction.