In 2010, the European Medicines Agency (EMA) has approved the lowest number of new drugs in the last decade. This is not surprising, considering that it takes at least 10 years to register a drug, the total cost is about one billion dollars, and that at least 9 out of 10 of those for which clinical development is initiated, fall by the wayside. Some striking example? Rimonabant for obesity and metabolic syndrome, the monoclonal antibody ocrelizumab for rheumatoid arthritis and systemic lupus erythematosus. But above all, a series of drugs that promised to change the evolution of a common and incurable disease such as Alzheimer. Among EMA approvals, cancer drugs are still leading: although it is now quite clear that they have little effect on mortality!
What's next for 2011? We can hardly expect any blockbusters: with the possible exception of antithrombotic drugs. And this is not trivial, because in Italy every year 400,000 people die or become invalid for diseases caused by occlusion of blood vessels by blood clots: myocardial infarction, stroke, venous thrombosis and pulmonary embolism. Neither is thrombosis sparing the developing countries: in 2015 there will be 50 million deaths worldwide due to thrombosis, and countries like China, India, Brazil and Russia will certainly not be spared.
Available antithrombotic drugs
Antithrombotic drugs are divided into two categories: anticoagulants, which slow blood clotting and are used mainly in vein thrombosis (phlebitis and pulmonary embolism), and antiplatelet drugs, which are used primarily in arterial thrombosis (myocardial infarction and brain stroke).
Is there need for new anti-platelet drugs, in addition to aspirin and clopidogrel? Clopidogrel, which is used in combination with aspirin in myocardial infarction and other coronary heart diseases, is ineffective in a proportion of patients ranging from 15 to 30%, because there are genetic variations that make their bearers insensitive to the antithrombotic action of this drug. The new antiplatelet drugs (prasugrel, ticagrelor) have the same antithrombotic efficacy of clopidogrel, but their action is entirely independent of the genetic variants that determine resistance.
Why is it necessary to develop new anticoagulants? Heparin and its derivatives, as well as dicumarols, have been used for a very long time, their antithrombotic efficacy is well known and they are inexpensive. Their limits are related to the route of administration for heparin and the need for laboratory tests for both. Intravenous or subcutaneous administration of heparin becomes a practical problem when the antithrombotic therapy is to be administered for a long time and at home. The dicumarols are administered by mouth, but the safe and effective dose varies greatly from patient to patient (and above all in the same patient). Blood coagulability must therefore be measured in the laboratory at least every 15-20 days, to prevent an excess inhibition of coagulation (and hence the risk of bleeding) or insufficient inhibition (and therefore the risk of new thrombosis).
The new anticoagulants
What are the new anticoagulants, and why do they represent a step forward? Dabigatran, rivaroxaban and apixaban are the most advanced in clinical trials, and have already been registered or registration is pending in many countries. The big advantage is that not only are they administered orally, but they also determine very predictable anticoagulant action at fixed doses, without the need for laboratory monitoring.
Is this a real benefit? Take, for example atrial fibrillation. It 's the most common cardiac arrhythmia, which affects about 1% of the over sixties and as many as 10% of the over eighties (in the aging Italian population this arrhythmia is rising steadily). Atrial fibrillation often leads to the formation of clots in the heart, their detachment (embolization) and the consequent occlusion of arteries (especially those in the brain), which cause highly debilitating strokes. The traditional anticoagulant therapy with dicumarols greatly reduces the risk of stroke, but continues to require laboratory tests. It is not easy for frail older people, who are the most affected by this arrhythmia, to travel frequently to laboratories to measure their blood coagulation status, and continue to change the dose of dicumarols in relation to changes in coagulation. The result of these difficulties is that more than 50% of them either do not use this uncomfortable therapy at all or they do not use it properly, with serious risks of bleeding or thrombotic complications. These new anticoagulants are at least as effective as the dicumarols in preventing embolic stroke, are at least as safe in terms of bleeding risk but, more importantly, they are administered in fixed dose without the need to continuously monitoring blood coagulation.
Is it true glory?
Are they a true "blockbuster" in the treatment of thrombosis? They are definitely a novelty and a substantial progress, but it will be necessary to wait for the field test in the common clinical practice, outside the selected situations in which controlled trials are conducted.
It will also be necessary to accurately assess their cost-effectiveness ratio, because, while it is certain that there will be cost savings associated with the elimination of the continuous medical and laboratory checks currently required with conventional drugs, there is no doubt that the cost of these drugs is much higher.