Over the past 10 years, recombinant hirudin has been proposed as an alternative to heparin in thrombosis prevention. Initial hopes of the usefulness of hirudin and analogues like hiralog, which have shorter active half-lives (around 30 minutes) compared to heparin, have been dashed by major studies like GUSTO IIb on more than 12,000 patients. These studies have not demonstrated any significant superiority of hirudin over heparin in the treatment of acute coronary syndromes.
Among other synthetic thrombin inhibitors under investigation, argatroban – an analog of arginine – has been shown to be an effective inhibitor of platelet activation by fibrin clot-associated thrombin, while Organon (Oss, the Netherlands) has developed an analog of pentasaccharide which in first trials has shown encouraging results as a pure factor Xa inhibitor for use in coronary angioplasty.
Roche's (Basel, Switzerland) oral antiplatelet therapy drug, sibrafiban, has been shown to be no better than aspirin in preventing cardiovascular events in at-risk patients. In the 9,233-patient Symphony trial, three studies failed to show significant benefits of sibrafiban, a glycoprotein IIb/IIIa receptor inhibitor when compared with aspirin. A Roche spokesperson said the company is still evaluating the Symphony results and will decide before mid-year what action to take. In the trial, aspirin was equally effective as sibrafiban in preventing further ischemic events, but additionally was less likely to cause major bleeding.
Searle (Skokie, Illinois) dropped two similar oral glycoprotein IIb/IIIa receptor inhibitors, emilofiban and orbofiban, in January 1999 after Phase III trials failed to show any benefits over aspirin.
NicOx's (Nice, France) speciality is grafting nitric oxide onto existing drugs to reduce adverse side effects and increase efficiency. The company has initiated Phase I trials with NCX 4016, a nitro-aspirin derivative. The clinical study will be performed on 24 volunteers and will compare three different formulations of NCX 4016 vs. aspirin. Preclinical studies indicate it may have a broader anti-thrombotic activity than aspirin. In animal studies, it has been shown to be more effective than aspirin for pain and inflammation relief.
Ramipril trial results have confirmed that the drug reduces cardiovascular events and reduces mortality among high-risk patients. In particular, the Heart Outcomes Prevention Evaluation (HOPE) substudy on 3,577 diabetic patients reported a 25% reduction in combined risk of heart attack, stroke, or cardiovascular mortality and a 24% reduction in nephropathy rates. AstraZeneca's (London) ramipril showed these benefits irrespective of whether patients were IDDM or NIDDM diabetics, or whether they were on insulin or oral drug therapy.
Gene therapy may also be helpful in reducing restenosis. Two recent sets of animal studies have shown promise, with researchers from Gencell (Vitry-sur-Seine, France), a division of Rhone-Poulenc Rorer, reporting the transplantation of the human apolipoprotein E (apoE) gene into mice has led to complete regression of fatty plaque deposits in mouse arteries. Mice that received the apoE gene also showed lowered levels of cholesterol and triglycerides and increased levels of beneficial high-density lipoproteins.
Researchers at the Bristol Heart Institute (Bristol, England) used gene therapy to reduce abnormal cell proliferation by 58% in newly grafted blood vessels in pigs following bypass surgery. Sarah George and her team have targeted the matrix metalloproteinases (MMPs) which trigger proliferation of smooth muscle cells in the grafted vessels, leading to restenosis. The team found that increased production of TIMP-3, an MMP inhibitor, reduced abnormal cell growth by 84% in human organ cultures.
Stents using surface modification
Polymer-coated stents, drug-loaded coated stents, and low-dose radioactive stents all have figured in recent trials on reducing restenosis after angioplasty.
Willem Van der Giessen and Patrick Serruys at the Thoraxcenter (Rotterdam, the Netherlands) have evaluated using Palmaz Schatz coronary stents which had undergone heparin attachment using the Carmeda (Stockholm, Sweden) ionic-attachment process. Serruys used these stents in the Benestent-II Piolet study in 1996 with some success.
Kadem Al-Lamee and his team at PolyBioMed (Sheffield, England) have evolved a new covalent-bonding process for the attachment of heparin through hydrophilic spacer arms onto the surface of metallic stents. Animal studies have shown that the covalent attachment of heparin onto a stainless steel surface resolved the problem of thrombosis, but did not reduce restenosis (neointimal hyperplasia).
Researchers at the Ulm University Hospital (Ulm, Germany) have worked with Al-Lamee to investigate using an anti-neoplastic drug like mitoxantrone covantly attached onto metallic stents. Initial in vitro studies have shown significant inhibition of smooth muscle cell growth. Al-Lamee said that animal trials would start shortly using stents covalently, coupled with a combination of heparin and mitoxantrone to address both thrombosis and restenosis problems. The Ulm University group also is starting up a second project to resolve these problems by covalently coupling radio-labeled heparin with sulphur (35S).
Population Biomedical Collection database
Half a million middle-aged (45 to 65 years old) volunteers are to be recruited onto a new British data base, the UK Population Biomedical Collection. The project will involve collecting lifestyle data, DNA samples, and compiled medical records.
The information will be used to disentangle the interactions between an individual's genes, social status and lifestyle and how this predisposes them to conditions like coronary heart disease, diabetes, and cancer.
The data can then be used by the pharmaceutical industry as an important resource for drug development and to clarify why some drugs work better in some patients than in others. The Biomedical Collection results from a concept by the Medical Research Council and the Wellcome Trust.
A panel, led by Professor Tom Meade, has been set up to study the project's feasibility, and to review major ethical problems like confidentiality and the linking of disease susceptibilities to different ethnic sub-groups. A National Health Service ethical committee will have the final say, but presently it seems likely the project will be under way early in 2001. Although it will take at least 10 years before the database begins to yield useful results, in scientific terms this is relatively short-term.
Researchers from the University of Tubingen (Tubingen, Germany) have used intravascular ultrasound guidance (IVUS) of angioplasty to reopen coronary arteries. In their trials on 178 patients with a 12-month follow-up, the researchers found a cumulative adverse event rate of only 12% and angiographic restenosis of 19%. The group used IVUS to measure accurately the external elastic diameter (as opposed to the lumen diameter usually measured with angiography) of the artery. The angioplasty balloon used was oversized (balloon-to-artery ratio greater than one), but did not produce the complications from damage to the vessel wall which have been experienced in earlier studies.
Commenting on the study, Jean-Pierre Bassand of the Centre Hospitalier Universitaire (Besancon, France) said that although this was only a single-center study, it shows that angioplasty with the balloon size determined by IVUS measurement produces results comparable with systemic stenting. "The attitude of extensive stenting prevails today despite the fact that it has never been demonstrated that stenting reduces immediate complications after angioplasty," Bassand said. He added, "The time has come to carry out randomized studies of IVUS-guided angioplasty. Some are already ongoing in Europe – it remains to be seen whether it is possible to escape from the 'pens e unique' [conviction] that coronary angioplasty must systematically involve stent implantation."