Clopidogrel is one of the first two drugs for which the Federal Joint Committee (G-BA) commissioned a cost-benefit assessment from the Institute for Quality and Efficiency in Health Care (IQWiG). According to calculations by INSIGHT Health, over 380,000 GKV patients in Germany are currently being treated with clopidogrel on an outpatient basis.

>> Clopidogrel is an active ingredient that inhibits blood clotting. As a so-called platelet aggregation inhibitor, it serves to prevent the formation of blood clots, which can cause blockages in the arteries and thus lead to a heart attack or stroke. The most frequently prescribed antiplatelet drug, with almost 5.6 million prescriptions, is acetylsalicylic acid (ASA). This is followed by clopidogrel with over 1.7 million prescriptions and the fixed combination acetylsalicylic acid + dipyridamole with just under 0.7 million prescriptions. The other active ingredients, including prasugrel, which was only approved in 2009, were prescribed a little over 100,000 times in the last twelve months (source: INSIGHT Health NVI, MAT November 2009).
One of the first two contracts to evaluate the cost-benefit ratio, which the G-BA recently awarded to IQWiG, deals with the analysis of clopidogrel. The IQWiG is intended to carry out a cost-benefit assessment of clopidogrel in combination with acetylsalicylic acid (ASA) in comparison to ASS monotherapy in acute heart disease and as monotherapy in comparison to ASS monotherapy in peripheral arterial occlusive disease (so-called intermittent claudication). Benefit assessments have already been completed, the results of which should be incorporated into the assessment. Some background information on the active ingredient clopidogrel and the debate is presented below.
According to calculations by INSIGHT Health, over 380,000 GKV patients in Germany are currently treated with clopidogrel on an outpatient basis, around a fifth of them receive a combination therapy of clopidogrel with ASA. Compared to the corresponding quarter of the previous year, there was a slight increase in the number of patients with clopidogrel prescriptions of almost two percent and for combination therapy by around three percent. More than 1.2 million SHI patients receive therapy with ASA (see Table 1).
The substance clopidogrel is largely prescribed by general practitioners (62.4 percent) and internists (33.2 percent). This also applies to ASA (65.9 or 31.4 percent), ASA + dipyridamole (69.1 or 24.7 percent) and prasugrel (59.9 or 37.3 percent). Over 1.7 million statutory health insurance prescriptions for clopidogrel last year resulted in a gross expenditure volume for statutory health insurance companies (excluding discounts, additional payments, etc.) of around 350 million euros, with a downward trend: -8.2 percent compared to the same period last year (Source: INSIGHT Health NVI, MAT November 2009). This means that the average gross drug expenditure per GKV insured person treated with clopidogrel on an outpatient basis is over 900 euros per year. However, there are now numerous discount agreements between the health insurance companies and the providers - on average around three contracts for clopidogrel per health insurance provider (!) - so that the net -Spending should be significantly lower (source: INSIGHT Health discount contract services).
The supply of clopidogrel is essentially ensured by the pharmaceutical manufacturers Sanofi-Aventis, Bristol-Myers Squibb, Hexal and Ratiopharm. The substance has an interesting history: The active ingredient clopidogrel received its EU-wide approval on July 15, 1998 under the product names “Plavix” (manufacturer: Sanofi-Aventis) and “Iscover” (manufacturer: Bristol-Myers Squibb). The patent protection did not extend to the active ingredient as such - as it had already been protected since 1988 - but rather to the salts used and the production process (see INSIGHT Health patent database). Manufacturers such as Ratiopharm and Hexal took advantage of the outlined gap in patent protection to bring the established active ingredient with a different salt onto the German market in the summer of 2008. These “generics” are around a third cheaper than the clopidogrel preparations from the original manufacturers (for price information see INSIGHT Health Price Monitor).
In the opinion of the manufacturers Ratiopharm and Hexal as well as some associations of statutory health insurance physicians and health insurance companies, the other salt form in which clopidogrel is administered has no influence on the effect, bioavailability or metabolism of the drug for patients (see e.g. KV Berlin: Information in the context the Medicines Agreement 2009 based on Section 73 Paragraph 8 SGB V - Information on the prescription of clopidogrel). This means that the same active ingredient would be available for patient care at a much cheaper price. In contrast, the original manufacturers such as Sanofi-Aventis stated in the discussion about comparability that a different salt with a restricted indication area was used and thus the proof of therapeutic equivalence was only partial (in patients with a heart attack, but not in patients with acute coronary syndrome) would be necessary (see e.g. Gräfe, Kerstin A.: Clopidogrel: Substituting - Yes or No?, in: Pharmazeutische Zeitung online, issue 33/2008). Since the summer of 2009, approval extensions have been available for most copycat drugs. This means that these can now also be used to treat patients with acute coronary syndrome.
The market entry of the clopidogrel products from Hexal and Ratiopharm nevertheless led to many patients early on - i.e. H. even before there was almost unlimited substitutability of original and successor products - to change the medication and to corresponding shifts in the new medication settings. While in the third quarter of 2008 only nine percent of clopidogrel patients were provided with these preparations (i.e. received at least one corresponding prescription), a year later this figure was already around 43 percent of patients (see Fig. 1). The additional indication areas did not lead to a sudden increase in market shares in the third quarter of 2009. New preparations already accounted for over half of new hires in the third quarter of 2009 (source: INSIGHT Health patient tracking).
In the future, clopidogrel patients will have to adjust to medication changes again due to active ingredient-related discount agreements. In the last AOK discount tender 2010-2012, the substance was removed “at the last minute”, but in other public EU-wide tenders such as the DAK tender, surcharges for clopidogrel can be expected. It can be assumed that the new generic competitors in particular are trying to gain market share with the help of exclusive discount agreements.
Cost-benefit assessment is crucial
In addition to the division of the clopidogrel market, the future development of the market potential for the active ingredient clopidogrel appears to be of utmost relevance for manufacturers. This will probably depend largely on the results of the upcoming cost-benefit assessment by IQWiG on the therapeutic approaches with clopidogrel and ASA. As part of the assessment, it should be considered whether the assumption of costs is “appropriate and reasonable” given the patient benefit that the medical intervention offers. The result of such an analysis could, for example, be evidence of a worse cost-benefit ratio of clopidogrel vs. ASA, which could have consequences for cost reimbursement or decisions and therapy instructions and thus prescribing behavior (e.g. prescription restrictions).
From a statutory health insurance perspective, treatment with clopidogrel represents a significant cost driver. Compared to therapy with ASA, clopidogrel involves significantly higher treatment costs. The prices of clopidogrel medications are up to a factor of 80 higher than the comparable price of acetylsalicylic acid (ASA).
While the daily therapy costs for ASA are in the order of a few cents, according to special analyzes by INSIGHT Health, these costs for clopidogrel can reach up to three euros.
One of the cost-oriented care goals therefore concerns the proportion of prescribed daily therapy doses (DDDs) of Clopido-grel in relation to ASA. According to KV Berlin guidelines, this share should be reduced from 27.9 to 22.0 percent in 2009, for example. In its letter from May 2009, the KV Berlin points out that the data on the therapeutic value of clopidogrel has not changed, despite the diverse discussion about “generics” and the partial exclusion of therapy by the Federal Joint Committee. Acetylsalicylic acid remains the drug of first choice for chronic atherosclerotic diseases. This does not rule out the use of clopidogrel, for example in the case of contraindications or intolerance to ASA (see Berlin Association of Statutory Health Insurance Physicians: Drug Regulations - Information on the Prescription of Clopidogrel, May 2009). In their 2010 drug agreement, other KVs formulated the goal of increasing the proportion of inexpensive clopidogrel preparations in all clopidogrel and, in some cases, prasugrel prescriptions (see, for example, KV Westfalen-Lippe: Drug agreement according to Section 84 Para. 1 SGB V for the year 2010 for Westphalia-Lippe, December 2009; KVB information, 01-02/2010). However, a differentiated approach is required here.
On the other hand, significant benefit values of clopidogrel have been documented, also by IQWiG: Monotherapy with clopidogrel has an additional benefit compared to treatment with ASA in patients with symptomatic peripheral arterial disease in terms of reducing the risk of vascular/thromboembolic disease Events (see IQWiG 2006: Final report Clopidogrel versus acetylsalicylic acid; Final report A04/01A).
According to IQWiG, the combination therapy of acetylsalicylic acid (ASA) and clopidogrel can reduce the risk of heart attack in acute coronary syndrome (cf. IQWiG 2009: Clopidogrel plus ASA in acute coronary syndrome; final report A04-01B). Here (as with myocardial infarction), in contrast to monotherapy, there is unrestricted reimbursement by the statutory health insurance, although cheaper alternatives are available (see, for example, KV Westfalen-Lippe: Overview - The use of clopidogrel, September 23, 2009).
Standard of comparison not uniform

Criticism of the IQWiG procedure for cost-benefit assessment is inevitable in advance. In contrast to its Anglo-Saxon counterpart, the output measure developed by IQWiG is not cross-indication. This can lead to discussions in the comparison between individual indications, as no uniform comparison standard is defined (cf. e.g. Staeck, Florian: The world formula for cost-benefit studies could ultimately be the competition, in: Ärzte Zeitung, December 22nd .2009). For example, by looking at England and the NICE cost-benefit assessments, it can be seen that issuing recommendations based solely on cost-benefit assessments does not per se lead to effects in prescribing behavior and thus on the cost side. Rather, it can be deduced that the “education” and “compliance” of doctors and patients must also be sustainably promoted. The medical and at the same time economic sense of recommendations must therefore be communicated sufficiently broadly and emphatically (cf. e.g. WINEG: “Cost-benefit assessment of medicinal substances - What can Germany learn from Great Britain?”). It therefore remains exciting to see whether and to what extent cost-benefit assessments will shape the design of the healthcare system in general and the use of the active ingredient clopidogrel in particular in the future. <<
By: Christian Bensing/
Dr. André Kleinfeld*