Update, February 7, 2005 - In an interview on February 4, an AstraZeneca representative told heartwire that the treating physician now believes the death was caused by an infection associated with neuroleptic malignant syndrome.
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New York - Pharmaceutical giants Pfizer Inc and AstraZeneca PLC, the makers of atorvastatin (Lipitor®) and rosuvastatin (Crestor®), respectively, are both feeling some heat with regard to their cholesterol-lowering medications. Pfizer is facing a legal attack on its patent by a relatively unknown generic drug maker, while reports of a patient dying while taking rosuvastatin have surfaced in the UK.
AstraZeneca has said the death was possibly caused by rhabdomyolysis. The company did not return calls to heartwire, but spokesperson Steve Brown told Reuters the details of the death were complicated.[1] He would not comment on what dose the patient was taking but did say the company still believes the safety profile of rosuvastatin is similar to other statins on the market.
Undoubtedly, the recent death adds more fuel to critics of the newest statin. Public Citizen, a Washington, DC-based watchdog group, has already petitioned to have the drug banned, and FDA official Dr David Graham identified rosuvastatin during Senate testimony in November 2004 as one of a handful of drugs currently on the market that pose a possible risk for patients.
Pfizer's problems are of a different nature, with a real-life David-vs-Goliath drama unfolding in the US District Court of Delaware. An almost unthinkable decision—that Pfizer could lose patent protection of Lipitor well before it is set to expire in 2009 and 2011—has some Wall Street analysts saying the risk of a Pfizer loss is "underappreciated" by most investors.
Ranbaxy Pharmaceuticals, a generic drug company based in New Delhi, India, challenged two patents that Pfizer says protect the statin medication. According to a report in the Wall Street Journal, Ranbaxy argued the first patent didn't expressly cover components of a molecule that Ranbaxy is now using to mimic Lipitor.[2]
It also argued that Pfizer never should have received a second patent on an updated version of this molecule because it was too much like the older one. In its defense, Pfizer has said the new molecule showed a significant advantage in lowering cholesterol over the older molecule and thus should be patented. Ranbaxy countered that Pfizer analyzed only data that backed this claim up, and if all the data were taken into account, the advantage of the newer molecule would be statistically insignificant. Because of this, the second patent is illegitimate, argued the New Delhi-based company.
Before the trial started, Ranbaxy had not been expected to win the case, but over the course of the two-week trial that view changed. Judge Joseph Farnan questioned witness testimony by a Pfizer scientist, possibly damaging his credibility. Pfizer did not return calls to heartwire, but the company told the Journal that both patents are valid and it expects them to be upheld.
A decision is expected in the next six to 12 months.
Sources
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Reuters. Cholesterol drug linked to a death. New York Times, January 11, 2005. Available at: http://www.nytimes.com.
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Abboud L. Challenge to Pfizer's Lipitor has some investors worried. Wall Street Journal, January 11, 2005. Available at: http://www.wsj.com.
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February 9, 2005 08:31 (EST)
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Crestor
If you look at mortality rates do to statin use Crestor should have had 8 to 9 deaths by now. The death of this patient wasn't caused by crestor. Public Citizen needs to obtain real data that would hold some merit before making accusations that are false and misleading. |
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February 10, 2005 10:30 (EST)
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Crestor has best Benefit-Risk Ratio
First of all, the details of the "death" associated with Crestor have been officially summarized as, "The most likely cause of death, in the treating physician's opinion, was infection not related'' to Crestor.
Secondly,Crestor has been subjected to unprecidented scrutiny as a result of being released after the Cerevastatin debacle, which means that we would expect a significantly increased reporting of side effects, yet it still has no deaths at 17,000,000 prescriptions (Cerivastatin had 31 associated deaths at 10 million prescriptions). Crestor also has an unprecidented amount of research at this point in its launch to support its safety and efficacy. No other statin can claim this kind of benefit:risk ratio.
Finally, a GP is not likely to ever see a case of rhabdomyolysis in his entire career, let alone a fatal one. So please, let's give this drug it's fair cudos and stop talking about compatively irrelavent issues! |
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February 10, 2005 06:01 (EST)
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Depends on what the definition of the word "is", or efficacy, is
If efficacy is potency of LDL reduction, the rosuvastatin is efficatious. but if efficacy is reduction in clinical hard endpoints then that remains to be seen. With other truely efficatious statins available, the role of rosuvastatin should be limited to those refractory to other statins. Even if one feels strongly about LDL reduction as "the " surrogate for improved outcomes, smiva/ezetimibe is another powerful option |
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February 11, 2005 12:35 (EST)
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Agreed up until the last sentence
Hisham,
I agreed with what you wrote up until the last sentence. Simvastatin/ezetimibe has no more hard clinical endpoint data than does rosuvastatin. Probably the only people who should be on these zebras (crestor or simvastatin/ezetimibe) are patients with very high-grade hypercholesterolemia who are being closely managed and monitored in lipid treatment clinics. They are certainly not the first or second line resort. We still need data. |
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February 11, 2005 01:28 (EST)
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Reply re Hisham's surrogate endpoints vs outcomes argument
First of all, let me say that I work for AstraZeneca (so I am probably biased) but that this is not an official company statement and may not reflect the views of the company.
Do you actually doubt that decreasing LDL decreases events? In the light of existing data, that seems a pretty weak argument. The extent to which you reduce LDL, whether you do it with statins, diet or even surgery, correlates almost perfectly with the extent to which you reduce CVD events and death. Look at HPS, Proove it, framingham, PROCAM, etc. Why do you think virtually every G8 national health care authority suscribes to cholesterol targets and they are going to be getting lower?
You could make an argument for mortality outcome data if you could show me ONE example of a treatment that lowered LDL and didn't lower mortality or events but since there are no major exceptions, the logical decision is to go by the recently coined proverb, "lower is better". |
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February 11, 2005 06:53 (EST)
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major exceptions
exceptions:
clofibrate - increased mortality and lowered LDL
estrogen/progesterone - increased mortality and lowered LDL
bezafibrate - lowered LDL, no prevention of cardiac events or stroke or mortality in two major trials (BIP and LEADER) |
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February 12, 2005 03:19 (EST)
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Response to Dan and to Mark
Hi Dan. Good to hear from you again. I certainly did not mean to imply that simva/ezetimibe has been shown to improve clinical outcomes, even though one might argue that since it does contain an ingredient that has been shown to significantly reduce events. I simply mentioned it as an alternative to rosuvastatin for those individuals that cannot reach goals with "clinically proven" statin therapy.
Mark. I can certainly understand your vigorous support of your product and appreciate your disclaimer Like you, I strongly believe that, at least in moderate and high risk individulas, the lower the LDL the better. However, it remains to be proven that aggressive LDL lowering in low risk individuals is beneficial. I have studied, not just looked at, HPS, PROVE-It, REVERSAL, etc. I learnt, that in addition to lowering LDL, atherosclerotic disease progression/regression (by IVUS in REVERSAL) and clinical outcomes (PROVE-It) were almost equally influenced by the level of "on-treatment" plasma CRP such that the best results were seen in those with lowest "on-treatment LDL and lowest CRP". Interestingly, in PROVE-It, there was no correlation between the magnitude of LDL reduction with that of CRP's.
In HPS, "predefined" subgoup analysis showed that the magnitude of LDL reduction did not correlate with improved outcomes.
I think we have a lot to learn as to how the various statins compare with respect to their ant-oxidant properties, their antithrombotic properties (effects on PAI-1, tissue factor expression), anti-inflammatory properties (not just plasma CRP levels but also CRP and other proinflammatory cytokines and chemokines produced within the plaque; remember that different statins have different hydrophilictites), effects on ameliorating apoptosis of various celluar elements within the plaque, ability to induce eNOS, ability to reduce insulin resistance and prevent development of new onset diabetes (only pravastatin has been shown to be clinically beneficial in that regard), effect on angiogenesis, etc....Thus to simplify the treatment objective to merely "lower LDL is better" is, in my humble opinion, overly simplistic. Add to that concerns about safety, especially lack of long term data, with rosuvastatin and for that matter, with statin/ezetimibe combo, it seems to me that one should stick with what one knows not what one thinks hew/she knows. Call me old-fashioned; call me a purist!!!!!
Regards,
Hisham |
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February 14, 2005 01:00 (EST)
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I was unconvinced by those reports.
Hisham and Mark,
The only thing I would add to Hisham's beautifully eloquent reply is that I was quite unconvinced by those reports in NEJM, ie the post-hoc analyses of PROVE-IT and REVERSAL, about the importance of CRP. The clinical applicability still puzzles me. Right now we would apply high-dose statins across the board in secondary prevention (especially post-ACS, given MIRACL, A to Z, PROVE-IT), and in high-risk primary prevention (diabetics, etc). Thus what is the point of measuring CRP at 28-30d and withdrawing or intensifying therapy at that point? Would anyone even do this?
Thus even if CRP has turned out to be a good predictor of which patients will benefit the most from statins after acute MI or in chronic CAD, it has only joined a myriad of other available predictors. If you have the disease, and it is manifest, you would offer optimal treatment even if the CRP was low; moreover, you would (hopefully) treat all risk factors (not just LDL). A very recent report in Archives shows just how variable CRP is in patients with STABLE CAD, with patients crossing risk strata (eg, high to moderate risk and vice versa) over time, due to fluctuations in concentration of the molecule.
Meta-analytic overviews of all statin trials show that on average, lower LDL concentrations correlate with better outcomes. However, not all variability in outcome is explained by on-treatment LDL reduction. In addition there are so few trials comparing equipotent doses of different statins, or different doses of the same statin, on hard clinical outcomes. Thus I agree in the end analysis with Hisham that much uncertainty remains! |
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February 14, 2005 03:33 (EST)
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Response to Dan
Dan, as usual, I do agree with you. The point behind CRP was to bring up the issue that LDL is not the "end all or be all" when it comes to predicting clinical outcomes. It certainly was not meant to endorse the use of CRP measurement which especially beyond the first 8 to 10 hrs of the MI, is more of a measure of muscle necrosis rather than the underlying inflammatory process that triggerred the thrombotic event in the first place. |
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February 21, 2005 02:55 (EST)
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Rosuvastatin eNOS & CRP
Rosuvastatin also has been clearly shown to decrease CRP equivalently or more than Atorvastatin (depending which study you look at). It has also been shown to cause NOS-induced vasodilation.
Dan, was LDL a PRIMARY outcome in those studies? Fibrates have their major significant effects on HDL and trigs, which lessens the independent effects of lowering LDL.
Re unconviced about CRP - look at Harvard Women's Health Study & Physician's Health Study. CRP correlates at least as well with risk as LDL (although obviously not as many studies corroberate this). Yes, it is variable but represents a distinct independent risk factor when LDL is not predictive and thus has solid diagnostic value.
It's funny, when Atorvastatin became the best-selling statin in the world, it still didn't have outcome data and barely anyone one challenged the belief (even then) that this would lead to decreased events and mortality. Now all of a sudden, eveyone wants end point data!?!?
Bottom line - does anyone really believe that Rosuvastatin will not significantly reduce mortality and CVD events when the data becomes available? Of course you don't, because you know that statins reduce cholesterol commensurate with the degree to which they lower LDL - the data is clear about this. |
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