In patients who have suffered a stroke, the combination of the two anti-clotting drugs dipyridamole and acetylsalicylic acid (ASA) is not superior to ASA or clopidogrel alone. The combination does not offer patients advantages, for example, in terms of a lower rate of complications or recurrence of stroke. However, the data provide proof of greater harm, as especially major bleeding is more common with dipyridamole plus ASA. This is the result of a final report published on 11 April 2011 by the German Institute for Quality and Efficiency in Health Care (IQWiG).
Treatment is intended to prevent further strokes and complications
When someone suffers a stroke, suddenly parts of the brain are no longer provided with sufficient oxygen. In most cases the stroke is caused by vessel calcification or a dislodged blood clot (ischaemic stroke). Patients who survive a stroke often suffer further strokes. In addition they have a high risk of other cardiovascular complications, such as heart attacks. Specific prevention for complications (“secondary prevention”) therefore plays an important role. Among other things this involves the use of drugs that prevent the blood from clotting too quickly. Drugs from the class of thrombocyte aggregation inhibitors inhibit the function of the blood platelets (thrombocyte= blood platelet; aggregate = to gather into a mass). They prevent the platelets from sticking to damaged blood vessels or to each other, which can lead to the formation of blood clots and occlusion of the vessel.
Three important drugs from this class are ASA, clopidogrel and dipyridamole, whereby ASA can be viewed as the most well-known and most thoroughly investigated platelet inhibitor.
In an earlier report, IQWiG had already assessed the benefit of clopidogrel (compared to ASA) for secondary prevention in patients with heart and/or vascular disease. According to the report’s findings there is no proof that clopidogrel offers an advantage over ASA in patients who have previously suffered a stroke.
Comparison with other drugs and placebo
The drug dipyridamole has been known for several decades. In Germany, it is only approved for secondary prevention after (ischaemic) stroke in combination with ASA. This combination therapy, which was developed by Boehringer Ingelheim and has been marketed since 2002 under the name of Aggrenox®, is recommended for the treatment of ischaemic stroke in several clinical guidelines. However, the risks of dipyridamole have been a topic of controversy in research for a long time.
The Federal Joint Committee (G-BA) commissioned IQWiG to assess the potential benefit and harm of combination therapy in patients after a stroke or transient ischemic attack (TIA). A TIA is a kind of “mini-stroke” with transient symptoms typically resolving within 24 hours. In the assessment, dipyridamole plus ASA was to be compared with placebo as well as other drugs.
Manufacturer provided all requested study data
IQWiG was able to include a total of 6 randomized controlled trials (RCTs) in the benefit assessment. Three studies were short-term (7 to 30 days), the others lasted between 1 and 4.5 years. In some studies dipyridamole plus ASA was compared to placebo and in other studies to individual drugs (ASA or clopidogrel). One study was previously unpublished. However, the study sponsor Boehringer Ingelheim provided IQWiG with all the data requested, as well as with additional information on studies already published.
Negative benefit-harm balance compared to ASA and clopidogrel
Dipyridamole plus ASA did not perform better than the individual drugs ASA or clopidogrel: combination therapy neither reduced mortality rates more effectively than ASA or clopidogrel, nor was it more effective in the prevention of further strokes or other acute vascular diseases (e.g. heart attacks). Nor was dipyridamole plus ASA superior with regard to any other investigated patient-relevant aspects of treatment.
However, IQWiG did find proof of greater harm: patients undergoing long-term treatment with dipyridamole plus ASA especially experienced serious major bleeding more often; patients under the age of 65 also experienced more intracranial bleeding events. No differences were shown for other serious side effects (“serious adverse events”). Overall, however, study participants receiving combination therapy discontinued treatment more often due to adverse events.
Studies comparing dipyridamole plus ASA with placebo provided indications both of benefit and of harm: In long-term therapy, recurrent non-fatal strokes occurred less often; however, bleeding events were more common.
Combination drugs must be tested
Pharmaceutical companies develop combination drugs with the expectation that a greater benefit can be achieved than by the administration of individual agents. But combination therapy is in fact not always superior and in this case not reasonable, as this type of therapy may have effects that cannot be predicted from the effects of the individual agents. The benefit as well as the harm may be greater or smaller under combination therapy. This is due to the fact that the combination of agents can lead to mutual augmentation or attenuation.
For example, the IQWiG report on clopidogrel and ASA in the treatment of acute coronary syndrome showed that the benefit for patients increases through combination therapy: the risk of a heart attack may decrease measurably. However, the risk of bleeding and thus of potential harm increases. In contrast, clinical trials investigating the treatment of stroke have concluded that the harm caused by the combination of ASA and clopidogrel increases distinctly more greatly than the benefit. This combination treatment is not approved for the prevention of stroke.
Combination drugs must therefore be tested as such in clinical trials and compared to the individual agents.
Inclusion of the ESPRIT study would not change conclusions of the report
According to the commission awarded by the Federal Joint Committee, only those studies were included in which the drugs were used according to the approval status in Germany. This is necessary, as the benefit assessment is to reflect the German health care setting. For this reason the ESPRIT study could not be considered in the assessment. This study was alluded to in the commenting procedure on the preliminary report. However, in the test as well as control groups the drugs were not used according to the German approval status: for example, dipyridamole could be administered both in a free and in a fixed combination. In addition, ASA was dosed differently, usually lower. “Ultimately only 8% of study participants were treated as envisaged by the German approval status for the combination drug,” explains Dr Thomas Kaiser, Head of the Drug Assessment Department at IQWiG. “Due to the lack of appropriate studies we do not know whether different doses of ASA are equivalent, particularly also in cases where ASA is administered together with dipyridamole. We therefore could not consider the ESPRIT study,” says Kaiser. However, IQWiG assessed how the inclusion of the results of the ESPRIT study would affect the conclusions of the report: “The report’s conclusions would not have been different,” says Thomas Kaiser.
Procedure of report production
IQWiG published the preliminary results in the form of the preliminary report in September 2010 and interested parties were invited to submit comments. When the comments stage ended, the preliminary report was revised and sent as a final report to the contracting agency, the Federal Joint Committee, in February 2011. The written comments are published in a separate document at the same time as the final report. The report was produced in collaboration with external experts.
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