At the American Heart Association meeting in Orlando, FL they just released the results of the ARBITER 6 HALTS study. No Vytorin was used in the study, but I am sure that all the headlines will mention Vytorin... and for good reason.
Here is the actual study published ahead of press online in the New England Journal of Medicine. Essentially, the enrolled over 200 patients from Walter Reed and Washington Adventist (right in my home town!) who had known heart disease or were at very high risk. These patient were already on a stable dose of a statin (40-50% on simvastatin -half of the Vytorin combination, and 40-50% on Lipitor) with LDL cholesterols (bad cholesterol) under 100 and HDL (good cholesterol) under 50 for men/55 for women. These patients were randomized to receive either Zetia (the other half of Vytorin) or Niacin (though you can get this vitamin over the counter, patients received the extended release prescription version, whose maker is also the sponsor of the study). They were looking to see whether or not there would be difference in progression of atherosclerosis (clogging of the arteries) over 14 months as measured by carotid intima-medial thickness (CIMT), and ultrasound of the neck arteries which seems to be a good measure of plaque buildup in the coronary or heart arteries. News broke earlier this year that the study was stopped early because there was a clear winner, but we didn't know which drug won until now.
Patients who got the Niacin had their good cholesterol raised by close to 20%. bad cholesterol lowered by close to 10%. The Zetia group lowered bad cholesterol by close to 20% but also lowered the good cholesterol too. More importantly, those patients taking the Niacin had a reduction in the plaque buildup, whereas patients taking the Zetia had no change in plaque build up. Surprisingly, and inexplicably, the more Zetia lowered your cholesterol, the more plaque build up patients had. Finally, and most importantly, only 1% of patients in the Niacin group had major cardiovascular events, compared to 4% in the Zetia groups. This was statistically significant.
This trial has broader implications than just the Vytorin issue (which I will get to in a second). It suggests that patients at high risk for cardiovascular disease may have additional benefit beyond lowering their bad cholesterol. Though the addition of Niacin was proven to show benefit, it might be possible that other drugs which raise HDL such as fish oil and fenofibrate (Trilipix) might benefit at risk patients as well.
I have posted extensively on Vytorin in the past. Most of the controversy had to do with the ENHANCE trial which I discussed in my post Vytorin and Zetia: What to do now? Briefly, whereas multiple statin trials have shown that lowering LDL with a statin led to decreased heart attacks and stroke, Vytorin only had data showing it lowered the LDL. Merk, the makers of Zocor (simvastatin), Zetia, and Vytorin (Zocor + Zetia) funded a trial that, similar to the HALT study, looked at CIMT to measure plaque buildup. It compared simvastatin to the same dose of simvastatin plus Zetia, or Vytorin. Though Vytorin lowered cholesterol more that the simvastatin alone, there was no difference in plaque buildup. Defenders of Vytorin said that ENHANCE was not an outcome study (designed to study actual heart attacks and strokes) and that there were no differences in outcomes between the two groups. Though the HALT study was also not designed as an outcome study, findings were consistent AND there was a difference in heart attacks and strokes: about triple the number in the Vytorin group. My initial recommendation was that though Vytorin was really useless, if patients couldn't reach their goal with a potent statin or couldn't tolerate the statin, then using or adding Zetia was reasonable. This is probably still the case. However, in the HALT study differences were seen in HDL (went up for Niacin and down for Zetia), and this may account for some of the difference. For patients whose HDL was low, I will probably be a little more cautious of using or adding Zetia, which may make their HDL go down in addition to their LDL.
Bottom Line: There is no good use for Vytorin, and it may even cause harm, not because of safety, but because the LDL goals achieved with Vytorin may lead to fewer heart attacks that could be prevented with a more potent statin. If you are on Vytorin, ask you doctor about considering a switch.
Showing posts with label merk. Show all posts
Showing posts with label merk. Show all posts
Sunday, November 15, 2009
Sunday, July 26, 2009
Sick About Singulair
The New York Times' business section recently reported that despite a second-quarter earnings fall, hurt by lower sales of its cholesterol drugs (specifically Vytorin, see my posts on why you should no longer use this product), Merck actually beat profit forecasts due to good sales of its asthma drug Singulair. Singulair's quarterly sales jumped 16 percent to $1.3 billion. That's a lot of money! Indeed, based on pharmacy data (via drugtopics.com, thanks again Mr. Medsaver for this great resource), Singualir was the 4th most commonly prescribed drug in 2008 at a close to 26 million prescriptions! Moreover, a recent report from the WSJ Health Blog states that Merk is looking to put Singualir over the counter.
I have no ill will towards Merk. It is an American company that has come up with some products that I find beneficial for patients including Fosamax (which is now generic) and Januvia, and they are the makers of two important vaccines: Gardisil and Zostavax. However, I am concerned about high sales of the asthma drug Singulair, because national guidelines state it should not be used as a first line therapy for asthma.
Facts about asthma
According to the American Lung association, in 2007, it was estimated that 22.9 million Americans currently have asthma. Of these, 12.3 million Americans (3.8 million children under 18) had an asthma attack. In 2005, there were 3,884 deaths attributed to asthma. During 2006, 444,000 hospitalizations and close to 1.7 million emergency room visits were attributed to asthma.
In 2007, the NIH released updated guidelines about asthma. Regarding treatment, the guidelines suggest that all asthmatics with persistent asthma (symptoms or rescue medication use more than twice a week) be initiated on inhaled corticosteroids (ICS). ICS's are considered first line treatment for all asthmatics, from babies to children to adults and to the elderly. The reason is based on solid evidence that these agents work the best in improving lung function and decreasing symptoms. Singulair is listed as an alternative agent. Singulair is an anti-leukotriene. Leukotrienes, like histamines, are substances released in an allergic response that cause the airways to tighten up. Thus, Singulair works in the same way that antihistamines work: by treating the symptoms. ICS's work by blocking inflammation which is what causes the release of leukotrienes in the first place. Singulair is not anti-inflammatory, ICS's are. Singulair treats the symptoms, whereas ICS's treat the problem. This is why study after study proves that ICS's are superior to Singulair, and why guidelines place ICS's as first line treatment and Singulair as alternative.
Does Singulair work?
Of course Singulair works. In order for a drug to be approved by the FDA, the drug company has to show that its product is efficacious. The problem is that it has to show that it is efficacious compared to placebo. Thus, Singulair works better than a sugar pill. However, compared to any other asthma medication, it is not as good. Even when added on to an ICS, it is not as good as other add ons, such as long acting beta agonists (LABA's).
Why do physicians prescribe so much Singulair when is not what the guidelines recommend?
What about allergies?
Singulair is also indicated for allergic rhinitis or allergies. As above, like histamine, leukotrienes play a role in allergic rhinitis, and this is why Singulair is used. I have posted about Singulair and allergic rhinitis previously. Basically, there are several treatments for nasal allergies:Non-sedating antihistamines (Claritin, Zyrtec, Allegra), Leukotriene modifiers (Singulair), inhlaed nasal steroids (Flonase or fluticasone, Rhinocort, Nasacort, Veramyst) and inhaled nasal antihistamines (Astepro). Muliple studies that show that fluticasone (Flonase) is better than Singulair, better than Claritin, and several studies that show that the combination of Singulair and Claritin is not better than either agent alone. However, in one study, though the combination of Singulair and Claritin was better than either agent alone, the individual agents were no better than placebo. An excellent review by Dr. Robert Nathan showed that "leukotriene receptor antagonists (Singulair) are sometimes more effective than placebo, are no more effective than nonsedating antihistamines (Claritin) , and are less effective than intranasal corticosteroids in the treatment of allergic rhinitis." Finally, a recent guideline from World Health Organization suggests that for patients with mild, intermittent allergic rhinitis; treatment with non-sedating antihistamines and leukotriene modifiers were both acceptable forms of treatment, but patients with more chronic or bothersome symptoms, inhaled nasal steroids should be used.
Some would argue that having both allergies and asthma together would be a reason to take Singulair. There is no question that treating allergic rhinitis may help with asthma symptoms. However, the killing two birds in one stone approach simply hasn't been proven to be the case. If you have allergic rhinitis that makes your asthma worse, you should take the most effective agent, which is inhaled nasal steroids.
What if I am taking Singulair for asthma?
Singulair has been proven more effective than placebo, and in some individuals controls their asthma and allergies. However, a recent internet survey revealed that about 55% of asthmatics have uncontrolled asthma, and many of them are on regular medications. Asthma control is the key, according to the new NIH guidelines. If your asthma is well controlled on Singulair, then it is probably OK to take. However, there is a theoretical risk that by taking Singulair (treating the symptoms without treating the underlying inflammation), that though you feel well now, your lung function will be worsening over time. More importantly, if you are taking Singulair and your asthma is not well controlled, then you should definitely switch to at least an inhaled corticosteroid, or possibly an agent combining an ICS with a long acting brochodilator (LABA) such as Advair or Symbicort. There are many ways to determine asthma control, including how much rescue medications you are taking and how asthma affects your daily life. The easiest way to determine your asthma control is by taking the Asthma Control Test
I have no ill will towards Merk. It is an American company that has come up with some products that I find beneficial for patients including Fosamax (which is now generic) and Januvia, and they are the makers of two important vaccines: Gardisil and Zostavax. However, I am concerned about high sales of the asthma drug Singulair, because national guidelines state it should not be used as a first line therapy for asthma.
Facts about asthma
According to the American Lung association, in 2007, it was estimated that 22.9 million Americans currently have asthma. Of these, 12.3 million Americans (3.8 million children under 18) had an asthma attack. In 2005, there were 3,884 deaths attributed to asthma. During 2006, 444,000 hospitalizations and close to 1.7 million emergency room visits were attributed to asthma.
In 2007, the NIH released updated guidelines about asthma. Regarding treatment, the guidelines suggest that all asthmatics with persistent asthma (symptoms or rescue medication use more than twice a week) be initiated on inhaled corticosteroids (ICS). ICS's are considered first line treatment for all asthmatics, from babies to children to adults and to the elderly. The reason is based on solid evidence that these agents work the best in improving lung function and decreasing symptoms. Singulair is listed as an alternative agent. Singulair is an anti-leukotriene. Leukotrienes, like histamines, are substances released in an allergic response that cause the airways to tighten up. Thus, Singulair works in the same way that antihistamines work: by treating the symptoms. ICS's work by blocking inflammation which is what causes the release of leukotrienes in the first place. Singulair is not anti-inflammatory, ICS's are. Singulair treats the symptoms, whereas ICS's treat the problem. This is why study after study proves that ICS's are superior to Singulair, and why guidelines place ICS's as first line treatment and Singulair as alternative.
Does Singulair work?
Of course Singulair works. In order for a drug to be approved by the FDA, the drug company has to show that its product is efficacious. The problem is that it has to show that it is efficacious compared to placebo. Thus, Singulair works better than a sugar pill. However, compared to any other asthma medication, it is not as good. Even when added on to an ICS, it is not as good as other add ons, such as long acting beta agonists (LABA's).
Why do physicians prescribe so much Singulair when is not what the guidelines recommend?
This is an extremely important question. Some may chalk it up to drug company marketing. However, all the ICS and ICS/LABA making companies due their job marketing their product as well. I think the main reason has to do with fear of ICS's. Corticosteroids are different than the kind of steroids athletes take. However, they are not without side effects. Earlier studies on older medications showed some growth delay in children, which is why pediatricians may be so reluctant to use ICS's. However, more recent studies showed that for the newer agents, long term use with mild to moderate doses did NOT cause growth delay. In 2002, the NIH reviewed all the literature and determined that at low to medium doses of ICS's, there are NO SIGNIFICANT SIDE EFFECTS. This is when ICS's became considered first line therapy for ALL asthmatics.
The other issue is the convenience factor of a pill vs. an inhaler. Inhaler use is clearly not as easy as taking a pill (Singulair comes chewable for children).
The thought is probably, "it's a once a day pill that might help my patient, and probably won't hurt them, so why not give it try?" The problem with this approach, is the failure to consider the risks of uncontrolled asthma. Uncontrolled asthma leads to ER visits, hospitalizations, and possible even death. Asthma is a serious disease. For patients who have persistent asthma, following the guideline recommendations of ICS's as first line agents is the right thing to do.
What about allergies?
Singulair is also indicated for allergic rhinitis or allergies. As above, like histamine, leukotrienes play a role in allergic rhinitis, and this is why Singulair is used. I have posted about Singulair and allergic rhinitis previously. Basically, there are several treatments for nasal allergies:Non-sedating antihistamines (Claritin, Zyrtec, Allegra), Leukotriene modifiers (Singulair), inhlaed nasal steroids (Flonase or fluticasone, Rhinocort, Nasacort, Veramyst) and inhaled nasal antihistamines (Astepro). Muliple studies that show that fluticasone (Flonase) is better than Singulair, better than Claritin, and several studies that show that the combination of Singulair and Claritin is not better than either agent alone. However, in one study, though the combination of Singulair and Claritin was better than either agent alone, the individual agents were no better than placebo. An excellent review by Dr. Robert Nathan showed that "leukotriene receptor antagonists (Singulair) are sometimes more effective than placebo, are no more effective than nonsedating antihistamines (Claritin) , and are less effective than intranasal corticosteroids in the treatment of allergic rhinitis." Finally, a recent guideline from World Health Organization suggests that for patients with mild, intermittent allergic rhinitis; treatment with non-sedating antihistamines and leukotriene modifiers were both acceptable forms of treatment, but patients with more chronic or bothersome symptoms, inhaled nasal steroids should be used.
Some would argue that having both allergies and asthma together would be a reason to take Singulair. There is no question that treating allergic rhinitis may help with asthma symptoms. However, the killing two birds in one stone approach simply hasn't been proven to be the case. If you have allergic rhinitis that makes your asthma worse, you should take the most effective agent, which is inhaled nasal steroids.
What if I am taking Singulair for asthma?
Singulair has been proven more effective than placebo, and in some individuals controls their asthma and allergies. However, a recent internet survey revealed that about 55% of asthmatics have uncontrolled asthma, and many of them are on regular medications. Asthma control is the key, according to the new NIH guidelines. If your asthma is well controlled on Singulair, then it is probably OK to take. However, there is a theoretical risk that by taking Singulair (treating the symptoms without treating the underlying inflammation), that though you feel well now, your lung function will be worsening over time. More importantly, if you are taking Singulair and your asthma is not well controlled, then you should definitely switch to at least an inhaled corticosteroid, or possibly an agent combining an ICS with a long acting brochodilator (LABA) such as Advair or Symbicort. There are many ways to determine asthma control, including how much rescue medications you are taking and how asthma affects your daily life. The easiest way to determine your asthma control is by taking the Asthma Control Test
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