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Short acting and reversible effects made heparin a great anticoagulant

Heparin remains an important drug for venous thromboembolism. But, in some hospitals, a new era of oral agents has arrived. Jenny Bryan explains

By Jenny Bryan

Heparin remains an important drug for venous thromboembolism. But, in some hospitals, a new era of oral agents has arrived.  Jenny Bryan explains 

When medical student Jay McLean first reported the anticoagulant properties of “heparphosphatid” in 1916,1 he could not possibly have guessed at the extraordinary staying power of his painstakingly produced liver extract — later named heparin — as primary therapy in the treatment and prevention of venous thromboembolism (VTE).

Heparphosphatid was not even the focus of McLean’s work, and his supervisor, William Howell, recommended that the young researcher should initially report only on the coagulant properties of the brain extract, cephalin, which he had been tasked to investigate.2 Howell, a leading physiologist of his day, based at Johns Hopkins University, Baltimore, Maryland, believed that the chance finding with heparphosphatid should be further investigated before publication. But, knowing that he could not continue the research himself because of other commitments, McLean stuck to his guns and included heparphosphatid in his initial paper, although it was Howell who went on to give heparin its name and, thanks to his subsequent research on the substance, is more closely associated with the discovery.

“Heparin has been a great drug over the years because it is short acting and its effects can be quickly reversed with protamine if there is bleeding. But more sophisticated drugs are now coming through that will, at last, replace its main functions,” says Beverley Hunt, professor of thrombosis and haemostasis at King’s College London.

Decades of development

In the early 1920s, Howell produced heparin in more purified form and animal studies showed that it could prevent intravascular blood clots following thromboplastin injection. However, an early failure to show that heparin inhibited platelet agglutination, as well as coagulation, limited further progress. Charles Best, fresh from his successful collaboration with Frederick Banting on insulin, was determined that heparin should make as great an impact on thrombotic disease as insulin was already having on diabetes.

In 1929, he set up a research group in Toronto, Canada, which developed an even purer, more potent version of heparin. Using this product extracted from beef liver, the group showed that heparin, administered before and for long periods after mechanical or chemical injury to the intimal surfaces of blood vessels in dogs, could reduce thrombotic obstruction of peripheral veins.3 Early clinical use of the new, purer form of heparin showed efficacy in prevention of postoperative deep vein thrombosis (DVT),4 and the product entered widespread clinical practice just before the start of the 1939–45 war.

In 1947, one of the early pioneers of heparin use in clinical practice, Clarence Crafoord, reported results with approximately 800 patients treated with heparin post-operatively between 1935 and 1940, mainly after hysterectomy. “In the pre-heparin days there would have been a considerable number of cases of thrombosis in such a series, but actually there were almost no complications,” he said.5

In 1960, the first randomised trial was published demonstrating the efficacy of heparin in VTE.6 This showed a significant reduction in mortality associated with pulmonary embolism (PE) in patients treated with heparin and oral anticoagulants compared with no treatment.

Subsequent studies confirmed the efficacy of heparin and showed that continuous intravenous infusion was generally preferable to subcutaneous or intermittent infusions.7 In the years that followed, typical practice for hospital treatment or prophylaxis of VTE focused on initial treatment with heparin, followed by oral anticoagulants, such as warfarin, following discharge, for periods up to six months.7

Mode of action

Initial research had suggested that heparin’s main effects were through destruction of thrombin and inhibition of the conversion of prothrombin to thrombin, but later studies showed that this conversion could still take place in the presence of heparin.8 It was not until 1939, when heparin was already in common use, that further research showed that inhibition of thrombin formation by heparin required the presence of an additional substance now known to be antithrombin.8 Alone, neither heparin nor antithrombin exerted the desired effect but, together, they were shown to be highly effective in preventing thrombin formation.

The exact mechanism by which this occurs is now much better understood. By binding to specific sites on antithrombin — a single chain polypeptide synthesised in the liver — heparin induces a conformational change in antithrombin, which exposes a site that binds to and inactivates the coagulation enzymes, factor Xa and thrombin (IIa) in equal amounts and, to a lesser degree, factors IXa, XIa and XIIa, kallikrein, plasmin and C1-esterase. In this way, the anticoagulant effects of antithrombin are accelerated about 1,000-fold in the presence of heparin.7

Heparin versus warfarin

Heparin was well established by the time warfarin became widely available in the mid-1950s (PJ 2010;284:189). As an oral drug, warfarin had obvious advantages over heparin for long-term treatment, but its greater risk of bleeding was a significant drawback.

Professor Hunt points out that people may bleed with warfarin whether they are in or out of their international normalised ratio range and, whereas it is possible to reverse bleeding with heparin quickly, it is much harder with warfarin.
“In hospital, a short-acting, daily injection is more convenient for DVT prevention and for initial DVT or PE treatment. Once they get home, patients generally switch to warfarin for variable periods of time, depending on their co-morbidities,” Professor Hunt explains.

The arrival of LMWHs

In the mid 1970s, research showed that only 25–35 per cent of heparin bound tightly to antithrombin, but was responsible for 85–95 per cent of the anticoagulant activity of the drug.9 Clinical trials showed that fractions of heparin, low molecular weight heparins (LMWHs), were just as effective as unfractionated heparin in VTE but, because of their longer subcutaneous half-life, they could be given less often, and their more predictable anticoagulant response required little monitoring.7

“LMWHs took over from unfractionated heparin because they have predictable pharmacokinetics, only need to be given once a day instead of three times, and are less likely to cause problems such as heparin-induced thrombocytopenia and osteoporosis,” Professor Hunt explains. “Even so, unfractionated heparin still remains the gold standard in the US,” she adds.

Three types of LMWH (dalteparin, enoxaparin and tinzaparin) are available in the UK, all of which are indicated for DVT prevention in surgical and medical patients, and for treatment of DVT and PE.10 Dalteparin is also indicated for extended treatment and prevention of DVTs in cancer patients, and both it and enoxaparin have additional indications in unstable coronary disease.10 LMWHs are used off-licence for DVT prevention in pregnant women.

“There are few head-to-head studies of LMWHs, but they do vary in their molecular weight distribution, with some more like unfractionated heparins than others. Although most LMWHs have mainly anti-Xa activity, tinzaparin has greater anti-IIa activity. However, most trusts probably base their decision about which LMWH use on procurement costs and the extent of their licensing,” says Professor Hunt.

New era of oral agents

The oral thrombin inhibitor dabigatran was introduced in 2008 for post surgical VTE prophylaxis although, as Professor Hunt explains, it has subsequently been developed as a rival to warfarin for stroke prevention in patients with atrial fibrillation, rather than as direct competitor to heparin. In contrast, the manufacturers of the factor Xa inhibitors rivaroxaban and apixaban have initially put more emphasis on the VTE market.

In 2010, the EINSTEIN-DVT open label, randomised non-inferiority study compared rivaroxaban with enoxaparin followed by vitamin K antagonist treatment with warfarin or acenocoumarol for up to 12 months after a DVT.11 It showed that rivaroxaban alone was as effective as standard heparin and vitamin K antagonist therapy, with comparable bleeding rates.

A study of apixaban and enoxaparin for VTE prophylaxis following major joint replacement showed superior efficacy of apixaban and comparable bleeding levels.12

NICE has now issued recommendations for rivaroxaban and apixaban as options for VTE prevention following hip or knee surgery,13,14 and rivaroxaban for DVT treatment and DVT and PE prophylaxis.15

“All these newer agents have predictable pharmacokinetics so there is no need to monitor them, they are all available orally and there is no need to adjust the dose for the size of the patient, or for food or alcohol,” says Professor Hunt.
She predicts a sea change in approach to VTE treatment and prevention as more trusts — like her own — make a wholesale switch to one of the newer agents for anticoagulation therapy across all indications.

“It’s an exciting time [since] things are moving so fast. Heparin is still a staple for acute DVT and PE in many hospitals, but there is a move towards the newer agents. We will still use heparin in pregnant women because the newer agents haven’t been tested in pregnancy, and for patients with renal failure we’ll still need unfractionated heparin. So there are probably a few more years left in heparin yet.”

References

1 McLean J. The thromboplastic action of cephalin. American Journal of Physiology 1916;41:250–7.
2 Best CH. Preparation of heparin and its use in the first clinical cases. Circulation 1959; 19: 79-86
3 Best CH. Heparin and vascular occlusion. Canadian Medical Association Journal 1936;35:621.
4 Crafoord C. Preliminary report on post-operative treatment with heparin as a preventive of thrombosis. Acta chirurgica Scandinavica 1937;79:407.
5 Crafoord C, Gallie WE, Bauer G. Heparin in surgery. BMJ 1947;2:503.
6 Barritt DW, Jordan SC. Anticoagulant drugs in the treatment of pulmonary embolism: a controlled trial. The Lancet 1960;1:1309–12.
7 Blann AD, Khoo CW. The prevention and treatment of venous thromboembolism with LMWHs and new anticoagulants. Vascular Health and Risk Management 2009;5:693–704.
8 Brinkhous KM, Smith HP, Warner ED et al. The inhibition of blood clotting: an unidentified substance which acts in conjunction with heparin to prevent the conversion of prothrombin into thrombin. American Journal of Physiology 1939;125:683–7.
9 Beeler D, Rosenberg R, Jordan R. Fractionation of low molecular weight heparin species and their interaction with antithrombin. Journal of Biological Chemistry 1979;254:2902–13.
10 British National Formulary. January 2013. Low molecular weight heparins. Available at: hwww.medicinescomplete.com (accessed 25 January 2013).
11 EINSTEIN Investigators, Bauersachs R, Berkowitz SD, Brenner B et al. Oral rivaroxaban for symptomatic venous thromboembolism. New England Journal of Medicine 2010;363:2499–510.
12 Lassen MR, Raskob GE, Gallus A et al. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. The Lancet 2010;375:807–15.
13 National Institute for Health and Clinical Excellence. Rivaroxaban for the prevention of venous thromboembolism after total hip or total knee replacement in adults, TA 170, April 2009.
14 National Institute for Health and Clinical Excellence. Apixaban for the prevention of venous thromboembolism after total hip or knee replacement in adults, TA245, January 2012.
15 National Institute for Health and Clinical Excellence. Rivaroxaban for the treatment of deep vein thrombosis and prevention of recurrent deep vein thrombosis and pulmonary embolism. TA 261, July 2012.

Citation: The Pharmaceutical Journal DOI: 10.1211/PJ.2013.11116881

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