Effect of cessation of anticoagulant therapy on the course of ischaemic heart disease.

Abstract

While fierce arguments have raged round the place of anticoagulants in the management of ischaemic heart disease, evidence has been brought forward that, such treatment having been started, cessation may be hazardous (B.M.7., 1962). A number of reviews suggesting that the stopping of anticoagulant therapy may be followed by an increased thrombotic tendency have been published (Dinon and Vander Veer, 1960;Kuhn et al., 1961 ;Sise et al., 1961) and a possible theoretical basis has been suggested by Poller and Thomson (1964). Dinon and Vander Veer (1960) reported a series of 20 patients who sustained a myocardial infarction (the first infarction in 18 cases) and reinfarcted within one month of stopping anticoagulant therapy. Anticoagulants had been given for an average period of 40 days (range 24 to 82 days) and in most cases, therefore, the new infarction occurred at a time when the chances of such a relapse were still high. Kuhn et al. (1961), in a study of long-term anticoagulants in patients who had suffered myocardial infarction, noted a reinfarction rate of 5 % in the month following cessation of anticoagulants-this was higher than in any other month. However, the numbers involved-five reinfarctions (four of which were fatal)-were rather small and could be regarded only as suggestive.Sise et al. (1961), in a study of a large series of patients who had stopped anticoagulants, noted that among 45 instances where anticoagulants were stopped because of bleeding (and the patient was given vitamin K or a blood transfusion) there were 20 " relapses " (10 fatal and 10 non-fatal) in the following year, the largest proportion occurring in the first month. By contrast, in 53 instances when anticoagulants were given up because of difficulties in cooperating, because of the necessity for operation and for other non-urgent reasons, there were 15 " relapses " (seven fatal and eight non-fatal) in the subsequent year, and these appeared to be fairly evenly spread.The difference in the mortality rate in the first month was at the 5% level of significance, while if all relapses were considered the difference was at the 1 % level.These observations show that stopping of anticoagulants is associated with an increased thrombotic tendency only when cessation is because of haemorrhage. ObservationsThe present data were obtained during the course of a study of the effects of a low-fat diet compared with an ordinary diet on the progress of ischaemic heart disease. A consecutive series of men were used for the trial. They were all under the age of 65, had sustained one episode of cardiac infarction, and were subsequently free from serious complications such as persistent heart failure. Cases where the cardiac infarction was thought to be a complication of an existing disease-for example, diabetes or severe hypertension-were likewise excluded. Many of the men received up to 14 weeks' anticoagulant treatment but none were on long-term anticoagulants.

Increased risk of arterial thromboembolism after a prior episode of venous thromboembolism: results from the Prevention of REnal and Vascular ENd stage Disease (PREVEND) Study

“…This high risk was assigned to a rebound effect on coagulant factors (Grip et al, 1991;Genewein et al, 1996;Ascani et al, 1999). This notion, however, was not corroborated by others (Van Cleve, 1965;Sharland, 1966;Tardy et al, 1997) and therefore remains controversial. In our cohort, only one subject developed arterial thromboembolism within a month after cessation of anticoagulant therapy, indicating that the presence of a rebound effect is unlikely.…”

Rebound after cessation of oral anticoagulant therapy: the biochemical evidence

“…Indeed, some authors have identified 'high-risk groups' with a strikingly high relapse rate which include patients who were on long-term anticoagulation for > 2 years (Keyes et al, 1956;Van Cleve, 1965;Kamath & Thorne, 1969), patients in whom anticoagulation was stopped because of bleeding (Sharland, 1966;Sise et al, 1961;Thomes et al, 1960), patients with advanced atherosclerosis in general (Kuhn et al, 1961) and more than one myocardial infarction in their history (Nichol et al, 1958;Van Cleve, 1966) or patients with angina in the month preceeding cessation (Michaels, 1970). Indeed, some authors have identified 'high-risk groups' with a strikingly high relapse rate which include patients who were on long-term anticoagulation for > 2 years (Keyes et al, 1956;Van Cleve, 1965;Kamath & Thorne, 1969), patients in whom anticoagulation was stopped because of bleeding (Sharland, 1966;Sise et al, 1961;Thomes et al, 1960), patients with advanced atherosclerosis in general (Kuhn et al, 1961) and more than one myocardial infarction in their history (Nichol et al, 1958;Van Cleve, 1966) or patients with angina in the month preceeding cessation (Michaels, 1970).…”

“…The interpretation is difficult because the prethrombotic state may simply reappear (and is not transient) after a phase of suppression by oral anticoagulants as suggested by one study (Harenberg et al, 1983), or the pathological vascular process has silently proceeded further and becomes overt again; both types of events are not consistent with a transient overshooting of coagulation and subsequent normalization but rather with a 'catching up' to the initial or actual levels (Michaels, 1970;Wright, 1960Wright, , 1961. Nevertheless, a potential rebound phase, as suggested by the data of Grip et al (1991), may represent a prethrombotic state which could become manifest only in the high-risk subgroups (Sharland, 1966;Nichol et al, 1958;Michaels, 1970;Van Cleve, 1965, thus requiring a large patient population for its documentation. It may be for these reasons that more recent clinical studies have failed to reach significance (Grip et al, 1991) or are anecdotal observations (Beer & Schlup, 1986).…”

“…The controversy over the presence or absence of a rebound phenomenon after cessation of oral anticoagulant therapy now extends over more than three decades (Marshall, 1963;Liebermann & Lindner, 1965;Dinon & Vander Veer, 1969;Kuhn et al, 1961;Evans & O'Rourke, 1970;Hart & Coull, 1983;Carter et al, 1958;Sharland, 1966;Sise et al, 1961;Thomas et al, 1960;Keyes et al, 1956;Nichol et al, 1958;Michaels & Beamish, 1967;Beer & Schlup, 1986;Grip et al, 1991;Michaels, 1970;Côté et al, 1977;Van Cleve, 1965Kamath & Thorne, 1969;Wright, 1960Wright, , 1961Pickering et al, 1964) and it is still unclear whether or not the phenomenon is real. Recent reports on rebound angina pectoris and rebound coagulation after cessation of heparin (Theroux et al, 1992) or of thrombin inhibitors (Gold et al, 1993;Willerson & Casscells, 1993) have again focused on the topic.…”

“…A number of clinical studies appear to demonstrate a transient increase of thrombotic events after cessation of anticoagulation (Marshall, 1963;Liebermann & Lindner, 1965;Dinon & Vander Veer, 1969;Kuhn et al, 1961;Evans et al, 1970;Hart & Coull, 1983), whereas others do not (Côté et al, 1977;Van Cleve, 1965Kamath & Thorne, 1969;Wright, 1961;De Vries et al, 1980) or are not conclusive in this respect (Carter et al, 1958;Sharland, 1966;Sise et al, 1961;Thomas et al, 1960;Keyes et al, 1956;Nichol et al, 1958;Grip et al, 1991;Michaels, 1970;Pickering et al, 1964). The interpretation is difficult because the prethrombotic state may simply reappear (and is not transient) after a phase of suppression by oral anticoagulants as suggested by one study (Harenberg et al, 1983), or the pathological vascular process has silently proceeded further and becomes overt again; both types of events are not consistent with a transient overshooting of coagulation and subsequent normalization but rather with a 'catching up' to the initial or actual levels (Michaels, 1970;Wright, 1960Wright, , 1961.…”