Anticoagulation in patients with dilated cardiomyopathy

Incidence and Risk Factors of Thromboembolism in CHF

 * Early autopsy studies suggested that 37 – 50% of patients with Congestive heart failure (CHF) have evidence of Thromboembolism (TE).
 * More recent, retrospective, studies have found that the incidence of clinically apparent events is approximately 1.7 – 3.5 / 100 patient-years.
 * In the Vasodilators in Heart Failure (V-HeFT) trials, the overall rate of TE (including peripheral and pulmonary emboli) was between 2.2 and 2.5 / 100 patient-years, with stroke being much more common than either peripheral emboli or PE.
 * The only statistically significant predictor of stroke was a lower peak exercise oxygen consumption.
 * The presence of atrial fibrillation or flutter before randomization was not an independent risk factor for stroke.
 * The Survival and Ventricular Enlargement (SAVE) trial found that the incidence of TE was higher in older patients (63 + 9 yo vs. 59 + 11 yo, p < 0.001).
 * Although the overall incidence of TE was similar to the above studies, women were found to be at higher risk than men (2.4 events / 100 patient-years c/w 1.8 events / 100 patient-years).

Ejection Fraction

 * Patients with a post MI EF < 28% had a nearly twofold increase in the relative risk of stroke compared with patients with an EF > 28% (RR 1.86, p = 0.01).
 * For every 5% reduction in EF < 35%, the incidence of stroke increased by 18%.
 * In contrast to the above studies, the Studies of Left Ventricular Dysfunction (SOLVD) data only examined patients known to be in normal sinus rhythm at the time of randomization.

Left Ventricle

 * The presence of clot in the LV, as seen by echocardiography, has not panned out as a definite risk factor for the development of TE complications.
 * In a study by Ciaccheri et.al., none of the patients with intracardiac thrombosis had embolic complications, and no intracardiac thrombosis was found in the patients with emboli.
 * Kalaria et.al. followed 103 patients with dilated CMP, and found that although the presence of MR was equally present in patients with and without LV thrombus, none of the patients with LV clot had severe MR, and suggest that severe MR may actually be protective of thrombus formation.
 * In a study by Blondheim et.al., the prevalence of LV thrombus was 5.5 times higher in patients without MR as compared to those with MR (74% vs. 13%, p < 0.001).

Pathophysiology
In addition to a ‘low-flow state’ in the LA and LV, there is evidence that patients with CHF have a hypercoagulable state.
 * Levels of thrombin – antithrombin III complexes and D-dimers are elevated in patients with CHF.
 * The degree of hypercoagulability is related to the severity of CHF.

The Efficacy of Anticoagulation
Most of the anticoagulation trials in patients with CHF were observational, with patients being anticoagulated for a variety of reasons including AF, a prior TE event, and ‘attending preference’. Additionally, the level of anticoagulation was not controlled for in most of the studies.
 * Although a 1981 study by Fuster et.al. found that 18% of 104 patients who did not receive warfarin developed TE, c/w none of those who did, subsequent studies have not been able to confirm this.
 * In V-HeFT I, the TE rate was similar in patients regardless of warfarin therapy.
 * V-HeFT II, ironically, found an increased TE rate in patients receiving anticoagulation (4.9 / 100 patient-years c/w 2.1 / 100 patient-years, p = 0.01).
 * As the indication for anticoagulation was not controlled for, it is likely that the patients who received anticoagulation were thought to be at higher risk (i.e. had AF, known LV thrombus, or mechanical valves).
 * Likewise, although the SAVE trial found an 81% reduction in stroke among patients with LV dysfunction following MI who were treated with warfarin, anticoagulant therapy was not randomized and its intensity was not controlled.
 * SOLVD also failed to show a reduction in TE with warfarin.

Risks of Anticoagulation

 * Several studies (generally in patients with AF) have found the incidence of major hemorrhage in patients receiving anticoagulation to range from 2.3 – 6.8 / 100 patient-years.
 * The risk of intracranial bleeding is lower, and ranges from 0.62 – 0.9 / 100 patient-years.
 * Unfortunately, both the risk of TE and major bleeding seem to be higher in older patients.

The Benefits of Asprin
Again, there have not been any well designed randomized trial examining the role of aspirin as monotherapy in patients with dilated CMP.
 * Analysis of the V-HeFT data reveals a non-significant trend toward a lower incidence of TE in patients receiving ASA monotherapy when compared to patients who did not receive ASA or warfarin (see above graphs).
 * The SAVE trial, however, found that ASA reduced the risk of stroke by 56%.
 * In patients with an EF < 28% the risk reduction was 66% (p < 0.001).
 * SOLVD found a non-significant trend toward a lower TE rate in men, but a significant, 53% reduction in women (p = 0.03).
 * Again, however, it is unknown whether the patients who benefited from ASA in SAVE and SOLVD had underlying disease like AF.

Consensus
Based on the above facts, Loh recommends anticoagulation to patients with minimal risks for hemorrhage.
 * A dilated CMP and concomitant AF (based on the AF data, not the CHF data).
 * CMP with an EF < 40% following an MI.
 * Patients with symptomatic CHF requiring therapy with dig, diuretics and afterload reduction regardless of etiology.
 * The caveats however, are that patients with dilated CMP may have impaired hepatic and renal function, and often take multiple other medications that can interfere with warfarin, and therefore require more aggressive monitoring, and are at higher risk of bleeding complications.
 * Additionally, the level of anticoagulation has not been defined, and Loh generally aims for an INR between 1.8 and 2.5.