Beta-Blockers, ACE, PCSK9 Inhibitors and Statins in the Battle Against Heart Disease -Part II
Men and women can calculate their 10-year heart attack risk at a NIH Web site- http://health.nih.gov . There is an index, so go to the H for heart attack section. Use the "Health Check Tools" section to find "Heart Attack Risk Assessment" tool to calculate your heart attack risk level.e
(4/26/17) The results of a study that was published in a recent edition of the Journal of the American Medical Association (JAMA) Cardiology, that analyzed 29,932 Medicare patients ages 66 to 75 who had been hospitalized for a heart attack from 2007 through 2012 and had filled a prescription for either Lipitor or Crestor found that the majority of them had either cut back or stopped taking the medication after 2 years.
The senior author, Dr.Robert S. Rosenson, a professor of medicine at the Icahn School of Medicine at Mt. Sinai Hospital, said that by failing to take their medications properly, patients increased their risk for a heart attack, stroke and unstable angina,
(3/20/17)- The results of a study which was paid for by Amgen of its PCSK 9 bad cholesterol (LDL) lowering drug Repatha (evolocumab) found that it significantly reduced the chance that a high-risk patient would have a heart attack or stroke. The question arises though as to if it is worth the listed cost of about $14,523 a year, while generic statin medications cost pennies per pill/.
The results of the study were published in a recent edition of the New England Journal of Medicine. With generic versions of the statin drugs costing pennies, will the insurance companies approve payments for the usage of Repatha?
As we noted in our item dated 8/31/15 below, Sanofi SA and Regeneron Pharmaceuticals Inc. of Tarrytown, N.Y comparable PCSK 9 inhibitor drug Praluent costs about $14,600 per year.
The study involved 27,564 men and women , of whom about 80% had already had a heart attack, and the rest had previously suffered a stroke. Because they all had been taking statin medications before this study, their average LDL level was 93
(1/7/17)- A U.S. federal judge has ruled that Sanofi SA and its partner Regeneron Pharmaceuticals in the sales of their PCSK9 cholesterol lowering drug Praluent, had infringed the patent for Amgen’s Repatha. That decision permanently blocks Sanofi and Regeneron from selling Praluent in the U.S.
The Food and Drug Administration (FDA) had approved both of those drugs for sale in the U.S. in 2015. Both Sanofi and Regeneron said that they would appeal the decision immediately.
(11/15/16)- The U.S. Preventative Task Force recently issued a guideline in connection with the usage of statin drugs. The guideline approved their usage for those aged 40 to 75 who have 1 or more cardio vascular disease (CVD) factors.
The dosage should be low to moderate depending on the individual patient. The guideline was issued because the Task Force feels that statin usage is helpful in preventing CVD events.
(11/3/16)- Pfizer Inc. announced that it was halting any further development of its cholesterol drug bococizumab, a PCSK9 inhibitor in light of the fact that its Phase 3 clinical tests showed a decline in its efficacy over time and it had some tolerability issues.
As we noted in our item dated 8/31/15, both Repatha from Amgen Inc. and Praluent by Sanofi SA and its partner Regeneron Pharmaceuticals Inc. have gotten approval from the FDA to market their PCSK9 cholesterol fighting drugs, but both these pharmaceutical products are very expensive, since they cost over $10,000 per year.
On the other hand, the generic statin drugs that came onto the market after Pfizer’s patent life for Lipitor came to an end, are much cheaper and quite effective in the cholesterol battle The insurance carriers have been in the forefront of opposing usage of the fight against the PCSK9 drugs, when cheaper, effective medications are available.
As noted in our item dated 10/13/15 below, Pfizer’s CETPi cholesterol drug torcetapib also ended up in failure
(4/5/16)- Lilly & Co., released the date from the study of its failed drug evacetrapi that we wrote about in our item sated 10/13/15 below at the meeting of the American College of Cardiology’s annual meeting this past weekend.. The study involved 12,000 patients, and those in the study who did take the drug saw their LDL levels (bad cholesterol) fall to an average of 55 milligrams per deciliter from 84.
Their HDL levels (good cholesterol) rose to an average of 104 milligram per deciliter from 46. In spite of these impressive numbers 256 participants had heart attacks compared to 255 patients in the group taking the placebo. 92 patients who took the drug had a stroke compared to 95 in the placebo group.
434 people taking the drug died from cardiovadcular disease, such as heart attack or stroke, compared to 444 participants who were taking the placebo.
Stephen J. Nicholls, the study’s principal investigator and the deputy director of the South Australian Health and Medical Research in Adelaide was at a loss to try and explain why the drug had failed to meet its desired endpoints.
(10/13/15)- Lilly& Co. announced that the clinical trial study of its CETPi cholesterol drug was halted because it was clear that the data indicated evacetrapib failed to meet its end points. This was the third failure of this type of drug, following Pfizer’s torcetapib, and Roche’s dalcetrapib failures to prove efficacy
On the other hand this reinforces the PCSK9 cholesterol fighting drugs that have been approved by the FDA, as written about in out item dated 8/31/15 below.
(8/31/15)- The Food and Drug Administration gave its approval in July to Sanofi SA and Regeneron Pharmaceuticals Inc. of Tarrytown, N.Y. to begin sales of their LDL cholesterol lowering drug Praluent. It is to be marketed to people who are at high-risks of heart attacks that high dosage levels of statin drugs do not seem to be working. For more info on this matter, please see our item dated 6/17/15 below.
The list price for the drug will be about $14,600 a year. In clinical trials, Praluent lowered levels of LDL cholesterol by about 40% or more, even among patients taking statins. Praluent is an PCSK9 inhibitor category of drug that stifles a protein involved in cholesterol production.
The drug is self-injected every two weeks and comes in two available dosages. It is a monoclonal antibody, which is a protein made in genetically engineered living cells. It is also known as alirocumab, and it is similar to Amgen’s Repatha, or evolocumab, which won FDA approval to market its drug at the end of August. Repatha is expected to cost $14,100 a year
These 2 drugs belong to a powerful new drug class to lower the LDL cholesterol level for those who have extremely high LDL levels.
Both Repatha and Praluent work by targeting a protein called PCSK9 that interferes with the liver’s ability to clear cholesterol. For more info on this matter, please see our item dated 6/17/15 below.
(7/10/15)- The Food and Drug Administration (FDA) approved Novatis’ heart failure drug, known as Entresto, which had shown almost a 20% reduction in the risk of cardiovascular events when the results of its clinical trial study was announced almost a year ago.
Heart failure occurs in an estimated 5 million Americans, when the heart cannot pump blood adequately to the body’s organs. Entresto was known as LCZ696, and may replace angiotensin-converting-enzyme (ACE) inhibitors as the main treatment for chronic heart failure.
Novartis said Entresto would cost about $12.50 a day, with two tablets taken daily. The company is sponsoring another clinical study to see if the drug is effective for those suffering from preserved ejection fraction, which accounts for half of heart failure cases.
(6/17/15)- A Food and Drug Administration (FDA) advisory panel voted 13-3 in favor of Praluent, an LDL cholesterol lowering drug, from France’s drug maker Sanofi SA and Regeneron Pharmaceuticals Inc. of Tarrytown, N.Y. It is to be marketed to people with high-risk of heart attacks, such as people with very high cholesterol levels for genetic reasons caused by a condition called familial hypercholesterolemia.
The FDA usually follows the recommendations of its panels. It is an injectable medication administered once every two weeks, or once a month depending on the formulation, and is generically named alirocumab. Another similar medication called Repatha from Amgen Inc. will go before the same panel today.
This new class of medication is called PCSK( inhibitors. The medication blocks PCSK9, which is a protein that interferes with the liver’s ability to clear cholesterol (LDL) from the blood system. The exact pricing for the medication is unknown at this time, but health experts estimate it will run about $1,000 a month.
LDL levels dropped between 40% to 60% in the trials.
(3/20/15)- The early results of some small clinical studies of a new class of cholesterol drugs seem to be effective in sharply lowering the risk of heart attack and strokes. The two drugs used in the studies also sharply lowered the LDL (bad cholesterol) levels for those involved in the trials.
Both of the studies were sponsored by the manufacturers of the drugs in question, Amgen’s evolocumab and Regeneron Pharmaceuticals, in conjunction with the French drug manufacturer Sanofi’s. alirocumab, work by inhibiting a protein in the body called PCSK9 that helps regulate cholesterol.
The results of the studies were published in a recent edition of The New England Journal of Medicine. Dr. Jennifer G. Robinson, the lead investigator of the Regeneron-Sanofi trial stated: “To see a reduction in cardiovascular events already is very encouraging”.
(11/23/14)- The results of a 6-year study, that was reported on at the American Heart Association meeting in Chicago helped to clarify the role of LDL levels, with the lower that its level is at, the less the chance that there would be a serious heart event. The global study involved 18.144 heart patients in which Zetia, known genetically as ezetimibe was added to the statin drug simavastatin (Vytorin), and compared against simavastatin alone. Merck& Co. was the sponsor of the study.
Statins lower LDL levels by preventing it from being made. Ezetimibe lowers LDL levels by preventing cholesterol from being absorbed in the gut. Those on the combination of drugs were found to have an LDL level of 54 on average versus the 69.5 level for those on simvastatin and a placebo. Those on the combination drugs suffered no serious negative side effects.
Both groups ended up with very low LDL levels. There were 2,742 events in those taking simvastatin alone versus the 2,572 in those taking the combination drugs.
(9/3/14)- An analysis that was done retrospectively, and therefore can’t be relied on, provides the first evidence that targeting a protein known as PCSK9 could reduce the risk of cardiovascular events as indicated in our item dated 4/6/14 below. The drug alirocumab is being developed by Amgen and Pfizer. The drug, which is injectable, works by lowering the bad cholesterol (LDL) levels, but it will have to be subjected to a much larger trial group study.
Both groups of patients in the study received conventional ant-cholesterol statin pills in addition to alirocumab or a placebo. The placebo group suffered 3.0% major cardiovascular events versus 1.4% among the alirocumab group. There were 2,341 patients in the study, called Odyssey Long Term, which is expected to conclude next year.
(4/6/14)- The results of three phase III studies sponsored by Amgen Inc., an additional phase III trial from Sanofi SA and its partner Regeneron Pharmaceuticals Inc., and a phase II trial study from Pfizer Inc. that were reported at the recent annual meeting of the American College of Cardiology all showed promising results in connection with the drugs known as PCSK9 inhibitors in lowering LDL levels.
As noted in our item dated 3/18/14 below, the FDA has requested additional information from Regeneron re that neurocognitive ability may be impaired by patients taking the drug. LDL cholesterol levels being lowered by one-half to two-thirds for LDL have been reported so far in the trials.
PCKS9 drugs are bioengineered antibodies that block PCKS9, a protein that interferes with LDL clearance. The drug is injected and is not in pill form yet. It is a different drug than are the statin drugs in the battle against high cholesterol levels.
The ant-PCKS9 include Amgen’s evolocumab (Descartes), alirocumab from Sanofi and Regeneron and Pfizer’s bococizumab.
(3/18/14)- The U.S. Food and Drug Administration (FDA) has asked Sanofi SA and Regeneron Pharmaceuticals Inc., which are co-developing PCSK9 inhibitors, to assess the potential for their drug to cause neurocognitive adverse events. The pharmaceutical industry has hopes for this drug to be able to treat millions of patients whose high cholesterol isn’t well controlled by statins.
Amgen Inc., and Pfizer Inc., are two of the drug companies that are in the forefront of developing this type of drug to treat high cholesterol level patients. Regeneron had pointed out this adverse development in a February filing. Sanofi confirmed this development in a regulatory filing it made this past week..
The Sanofi-Regeneron drug is called alirocumab, and Regeneron said that it had not seen signs of neurocognitive damage in its clinical study.
(11/19/13)- The American College of Cardiology and the American Heart Association stirred quite a ruckus in announcing new guidelines as to whom statin drugs should be administered to. The new guidelines represented a sharp departure from decades of advice on preventing cardiovascular disease.
The new advisory no longer calls for just looking at the LDL and HDL numbers, nor do they even set levels at which the drugs should be administered. The new guideline calls for the usage of an online risk calculator to determine who should be on the statin drugs. Doctors are also being advised not to add other cholesterol lowering drugs to the statin regimen. The latest development has been the online risk calculator has been using outdated information, so it is not giving correct risk evaluation percentages.
The chairman of the committed that developed the new guidelines, Dr. Neil J. Stone of Northwestern University, said the committee was prompted to reexamine the theory that lowered LDL meant a lowered risk of having a cardiovascular event.
The new approach divides people into two broad risk categories. People with extremely high LDL, or 190 and above should be on the statin medications. If the online risk calculator evaluated a risk of at least 7.5%, that individual should also be on a statin drug. Family history, blood pressure, age and other illnesses are some of the keys used to determine risk levels. Now, if they can only get the data correct in the on line calculator, we My all have a better understanding where this mess is leading us.
(10/5/13)- From Science Daily: "A review of dozens of studies on the use of statin medications to prevent heart attacks shows that the commonly prescribed drugs pose no threat to short-term memory, and that they may even protect against dementia when taken for more than one year.
The Johns Hopkins researchers who conducted the systematic
review say the results should offer more clarity and reassurance to patients
and the doctors who prescribe the statin medications." (Their findings are
published in an online article in the Mayo Clinic Proceedings posted on October
(5/8/13)- The results of a study that was conducted on 1,001 patients in whom prostate cancer was diagnosed between 2002 and 2005 concluded that those patients who were taking statins have a lower risk of dying from the cancer than those who were not taking it.
The results of the study were published in a recent online edition of The Prostate. After controlling several variables, researchers found that people who did not use statins were 5 times as likely to die of prostate cancer than those who were taking the medication.
(1/3/13)- The question has arisen among medical professionals that will increasing an individual good cholesterol levels (HDL) result in less heart attacks or strokes. The results of a recent study of known as HPS2-THRIVE, which was independently conducted by the Clinical Trial Service Unit at Oxford University and funded by Merck & Co. concluded that no benefit resulted from increasing an individual’s HDL.
The study enrolled 25,673 patients considered to be at high risk for cardiovascular events. Patients in the study were followed for a median of 3.9 years.
The clinical trial compared extended-release niacin and laropiprant plus statin therapy versus statin therapy.
The study concluded that the combination of extended-release niacin and laropirant to statin therapy did not significantly further reduce the risk of coronary or stroke events.
Merck & Co. stated it would report details of the study results in the first quarter of 2013.
TREDAPTIVE/.CORDABTIVE has been approved in approximately 70 countries including Europe, and is sold in about 40 of those countries.
(10/16/11)- In our item dated 6/29/11, it was noted that an analysis of 5 clinical trial indicated that there was a higher risk of diabetes developing after taking statin drugs. Interestingly enough, the Food and Drug Administration (FDA) recently approved for sale the first combination medication that treats type 2 diabetes and high cholesterol in one drug.
The medication that was approved combines the active ingredient in Merck & Co.'s diabetes drug Januvia with another Merck drug, Zocor, a statin which is designed to lower high cholesterol. Merck will market the medication, Juvisync.
Januvia was approved in October 2006, and is designed to stimulate the pancreas to make more insulin, after eating a meal. Diabetes affects about 26 million Americans, a disease that increases the risk of heart disease.
(6/29/11)- The Journal of the American Medical Association recently published the results of an analyses of 5 clinical trials involving 32,752 patients that indicated that there is a 12% higher risk of diabetes developing as a result of taking statin drugs. Last year, the medical journal The Lancet published an analysis involving 90,000 patients that showed statin users had a 9% higher risk of developing diabetes than those who did not take the drug.
Dr. Steven E. Nissen, chairman of cardiology at the Cleveland Clinic stated, "What I worry about here is that people will read this story and say, 'I don't want to get diabetes, so I'm going to stop my statin', and then have a heart attack."
(5/29/11)- The medical and scientific community has long held to the belief that raising HDL or the good cholesterol level would be helpful in preventing heart attacks and strokes. This theory is known as the "HDL hypothesis".
A 3,414-patient study, called Aim-High was recently stopped before its scheduled expiration date because the theory just was not working for the patients involved in the trial. The drug used in the trial was Niaspan, which is an extended release form of Abbott Laboratories cholesterol raising drug niacin.
The patients involved in the study were high-risk heart patients who were also taking statins to lower their bad cholesterol levels (LDL). Patients in the study were given either the statin drug Zocor to lower LDL levels and a placebo, or Zocor and Niaspan and followed for 32 months. The trial ended 18 months early because it was found that there was almost no chance that taking Niaspan would prove beneficial
Niaspan rang up $927 million in sales for Abbott last year. The company spent $32 million on the study, and the government spent $21 million on it.
Adding Niaspan on average did increase HDL by about 20% and lowered triglyceride levels also, but there was not any significant reduction in heart attacks suffered by the patients on the combined drugs over those who were only taking the Zocor.
(1/26/11)- In a follow-up to our item dated 1/20/11 below, Merck & Co. said concerns about an increased risk of hemorrhagic stroke-or bleeding in the brain- in patients with a history of stroke led to its decision to halt its Tracer study and curb participation in its TRA-2P study of its anti-clotting drug vorapaxar.
Eugene Braumwald, of Harvard Medical School and Brigham and Women's Hospital in Boston, who headed the Data Safety Monitoring Board that oversaw the 2 studies told researchers on the 26,500 patient TRA-2P study that the board "observed an increase in intracranial hemorrhage in patients with a history of stroke that is not outweighed by their considerations of potential benefits."
That information led study leaders to discontinue participation of some 6,000 patients in the TRA-2P study with a history of stroke or who had suffered a stroke during the study.
Dr. Braumwald went on to say, the monitoring board recommended that "the trial continue to completion in the more than 20,000 subjects" who had a history of heart attack or peripheral artery disease, but not a stroke.
(1/20/11)-Merck & Co. announced that it was halting one of two major studies of its experimental heart drug vorapaxar and would curtail patient participation in the other study.
Vorapaxar, is an anti-blood clotting drug that had shown promise in preventing heart attacks and strokes without increased risk of bleeding.
The action was taken after the Data Safety Monitoring Board an independent data-monitoring committee that was tracking progress of both studies recommended the following actions:
Neither Merck nor the researchers leading the two clinical trials detailed a specific reason for the moves.
The TRACER study had been testing vorapaxar in combination with aspirin and Plavix, a widely used anti-clotting drug, in patient who were undergoing angioplasty and stent procedures or bypass surgery to clear or reroute blood around clogged coronary arteries.
Researchers at Harvard-affiliated Brigham and Women's Hospital in Boston led the TRA-2P study.
(11/19/10)- The early results of the clinical trial of Merck & Co.'s cholesterol drug anacetrapib, as reported in a recent edition of The New England Journal of Medicine are quite promising. The drug lowers the "bad" cholesterol level (LDL) while at the same time elevating the "good" cholesterol (HDL) level.
Anacetrapib works by inhibiting an enzyme called CETP, which helps to transform "good" cholesterol into "bad" cholesterol.
There were 1,623 patients involved in this study, and Merck is following up this study with a larger one that will involve over 30,000 patients, with the results being released in 2015.
Among the trial patients taking anacetrapib there was a 39.8% reduction in bad cholesterol beyond that seen in the placebo group. That same group had a 138.1% increase in "good" cholesterol compared to the placebo group.
According to Dr. Luciano Rosetti, the head of global scientific strategy at Merck Research Laboratories the important finding will be to see if the drug reduces the risk of heart attacks, coronary deaths and other heart problems.
The enlarged study will be coordinated by researchers at Oxford University and sponsored by Merck.
Pfizer Inc. conducted a trial of its CETP inhibitor drug called torcetrapib in 2004 that looked very promising at that time. After spending more than $800 million to develop the drug, Pfizer ended development in 2006, because study results showed the drug increased the risk of death by 59% and of heart attacks by 25%.
Dr. Rosetti said that Merck researchers closely examined the Pfizer drug to make sure there were no similar problems, such as increasing aldosterone levels, a hormone that can increase blood pressure.
(6/30/10)- The results of a recent analysis of data evaluated by researchers at the Veterans Affairs research center in Ann Arbor, Mich. suggests that the medical profession should use a range of factors, rather than relying solely on cholesterol level in determining who should be given statin medications.
Rodney Hayward was the lead author for the research project, the results of which were published in the January edition of the Annals of Internal Medicine.
The analysis shows that a more tailored approach to treating individual patients would be more beneficial than just trying to get LDL levels lowered. Each individual patient's heart risk evaluation should be based on a range of factors. These factors include family health history and conditions such as diabetes and hypertension, in addition to cholesterol levels would be a better approach than just looking at a numerical LDL level.
If the overall risk is high, subjects should get a statin, even if their LDL isn't much elevated.
(4/14/10)- According to the results of a study of Medicare patients that was published in the March 23rd edition of the journal Circulation, the rate of hospital admissions for heart attack was 23% lower in 2007 than in 2002. Jersey Chen, a Yale cardiologist was the lead author of the study.
The study showed that 228,170 fee-for-service Medicare patients were admitted to hospitals in 2007, down from the 297,653 that were admitted in 2002.
The report covered only the beneficiaries in the fee-for-service category of Medicare and did not include Medicare Advantage members. Heart disease continues to be the leading cause of deaths in this country.
(3/27/10)- Dr. James W. Black, the Scottish pharmacologist who discovered the usefulness of beta-blockers in preventing heart attacks, and also in the development of the anti-ulcer drug cimetidine, marketed as Tagamet, died recently at the age of 85,
The announcement of his death came from the University of Dundee in Scotland, but the cause and place of his death was not stated. Dr. Black was the chancellor of the University from 1992 till 2006.
Dr. Black was awarded the Nobel Prize for his work in 1988.
He led a team of researchers at the Imperial Chemical Industries, a company he joined in 1958, after working at the University of Glassgow till then. The first beta-blocker developed by his team was known as propanolol, which was marketed as Inderal
(2/11/10)- AstraZeneca PLC won approval from the FDA to market its cholesterol lowering drug Crestor with the claim that it could reduce the risk of heart attack, strokes, bypass operations and artery-clearing procedures in people with high levels of C-reactive protein, with at least one other risk factor.
The approval was based on the data from the Jupiter study that was financed by AstraZeneca, that we discussed in our items dated 11/27/09 and 7/27/09 below. Thus the drug can be marketed to people with healthy cholesterol levels, but other heart risks.
AstraZeneca claims that the drug can increase the good cholesterol level, while lowering the bad cholesterol level at the same time.
C-reactive protein is a sign of inflammation of the arteries associated with heart disease. Patients should be men at least 50 years of age or women at least 60, according to the FDA.
The rate of major cardiovascular problems was 1.2 percent for patients treated with Crestor, compared with 2.8 percent with a placebo.
Other risk factors includes high blood pressure, low HDL which is the "good cholesterol level", smoking or a family history of early heart disease.
(11/27/09)- The Jupiter study involved nearly 18,000 patients, and it compared patients on AstraZeneca PLC's cholesterol statin medication Crestor to patients receiving a placebo or fake pill. That study showed a 44% reduction in the number of adverse events including stroke, heart attacks, hospitalizations for heart problems and surgery to treat clogged arteries.
At a presentation given at the recent annual meeting of the American Heart Association, an analysis of about 6,800 women involved in the Jupiter study who had normal or slightly elevated cholesterol levels, but had an elevated C-reactive protein level, there was a reduction in death and other cardiovascular events of 46% after an average of two years on the women who were taking the Crestor only.
(9/27/09)- Dr. Paul M. Ridker, the director of the Center for Cardiovascular Disease at Brigham and Women's Hospital in Boston, who is also a paid consultant to AstraZeneca PLC had the results of his most recent study published in the journal Circulation: Cardiovascular Quality and Outcomes. You may remember Dr. Ridket for his study called Jupiter that we cite in our items dated 7/6/09, 4/11/09 and 11/19/08 below.
In the latest study that was funded by AstraZeneca, the maker of the statin cholesterol lowering drug Crestor, the researchers looked to compare the benefit of statin use in people with high C-reactive proteinlevels and low cholesterol levels as opposed to its benefit for people with high cholesterol and low C-reactive protein levels..
The researchers looked at how many patients with low cholesterol and high C-reactive protein would need to take Crestor for five years before the drug prevented a heart attack, stroke, treatment to unblock a clogged artery or death from a heart attack or stroke.
They found the number needed to treat, known as the NNT, was 20 patients. NNT is a common yardstick used by researchers to determine the number of patients who need to take a drug over time to derive a benefit over a five year period of time.
Dr Ridker said that in other prevention studies, the five-year NNT values for people with high cholesterol ranged from 44, for those taking the statin drug pravastatin or pravachol, made by Bristol-Myers Squibb, to 63 for people taking Merck's Mevacor, or lovastatin .
(8/9/09)- Merck & Co. and Schering-Plough have agreed to pay $41.5 million to settle class-action lawsuits that accused them of withholding the unfavorable results of the Enhance clinical trial of their cholesterol drugs Vytorin and Zetia. For more detailed information on this study, please see our item dated 8/6/08 below.
The companies failed to release the information from the study that showed that the combined drugs were no more effective in unclogging arteries than were older pre-existing medications used for this purpose.
The settlement resolves more than 140 claims filed by consumers and insurers who bought, used or paid money toward the purchase of Vytorin and Zetia. The consumer settlements require court approval.
The companies agreed, earlier last month, to a separate $5.4 million payment to the attorneys general of 35 states and the District of Columbia for costs incurred in investigating consumer-protection cases involving the drugs.
Merck and Schering have proposed a $41.1 billion merger of the two companies that they hope to finalize before the end of this year.
(7/6/09)- A paper that was published in a recent edition of The Journal of the American Medical Association, that analyzed genetic data from more than 100,000 people, concluded that their study "argued against" the notion that the elevated substance, C-reactive protein (CRP) causes heart disease. To see more on this matter please go to Part I of this article: Beta Blockers, ACE Inhibitors and Statins in the Battle Against Heart Disease or Failure-Part I dated 4/7/04.
Many health professionals believed that CRP caused heart disease, especially after a widely publicized study released last year suggested that people with low cholesterol but high CRP levels had fewer heart attacks if they took statin drugs that lowered their CRP levels.
Dr. Paul M. Ridker of Brigham and Women's Hospital in Boston, director of last year's study, called Jupiter, said the new study did not alter his viewpoint at all. Dr. Ridker, an inventor of a lab test for CRP who profits from its use, said that this study did not exclude CRP as a casual factor in heart disease. CRP goes along with inflammation, and it is inflammation that is likely to be causing heart disease, according to Dr. Ridker.
Dr. Paul Elliot of the Imperial College in London was the lead author of this new study.
Also see our item dated 4/11/09 below.
(4/11/09)- The primary results of the Jupiter study that we discussed in out item dated 11/7/08 below was that AstraZeneca's statin drug Crestor lowered the risk of heart attack by about 44%. A recent edition of the online edition of The New England Journal of Medicine, and at a presentation at the recent convention of the American College of Cardiology reported that a secondary finding was that Crestor reduced the risk of developing blood clots in the veins.
Venous thromboembolism, or VTE includes disorders called deep vein thrombosis, the blood clots that can form in the legs, and pulmonary embolism, clots that travel to the lungs with sometimes fatal consequences. This condition occurs most often in individuals who have a genetic defect known as Factor V Leiden and is often associated with long airline trips in which the individual does not get up and move around.
The findings are not necessarily correlated with the heart-related benefits. The Centers for Disease Control and Prevention estimates that up to 600,000 Americans get venous clots each year and that 100,000 die from them.
Dr. Paul M. Ridker, the director of the Center for Cardiovascular Disease at Brigham and Women's Hospital, who was the lead investigator for the study said that studying blood clots was a secondary purpose of the Jupiter study which was funded by AstraZeneca.
(12/24/08)- Abbott Laboratories announced that it had received approval from the FDA to start selling its cholesterol and triglyceride lowering drug TriLipx..TriLipx is made from the active component of TriCor, the Abbot drug that garnered $1.3 billion in sales last year, but whose patents begins to expire in 20011. Abbot is hoping to shift patients who are on TriCor over to TriLipx before the TriCor patents lapse.
TriLipx, is part of a drug group called fibrates, and is the first cholesterol medicine in its class to be approved for use with statin medication. Lowering cholesterol and a type of fat, or lipid, called triglyceride are thought to lead to a decrease cardiac events.
Abbott conducted separate studies showing that the combination of TriLipx with the generic version of Merck's statin medication Zocor as well as Pfizer's cholesterol lowering statin medication Lipitor and AstraZeneca's cholesterol lowering drug medication Crestor, yielded improvements in HDL and LDL cholesterol levels and in triglycerides.
Abbott recently settled litigation in which the plaintiff alleged that the company tried to prevent generic competition against TriCor by using a strategy called "product switching" in which the company phased out an existing drug and replaced it with a modified, "improved" version that prevents automatic generic substitution. Here we go again with the drug companies!!!!!!!!!!!
(12/6/08)- The NY Times recently carried an article by Andrew Pollack entitled: "A Big Blood Pressure Study, and Its Minimal Impact on Drug Use". The article dealt with the clinical study called Allhat, and shows how diuretics have failed to gain market share in a crowded drug market in helping to reduce the risk of heart problems.
Paul Whelton, senior vice-president of health-science at Tulane University led the study. We have highlighted in some of the items below this one in red, and also in Beta Blockers, ACE Inhibitors and Statins in the Battle Against Heart Disease or Failure-Part I of this series of articles what the Allhat study entailed.
As Mr. Pollack points out in his article: "Six years later, though, the use of the inexpensive pills, called diuretics, is far smaller than some of the trial's organizers had hoped."
He went on to point out: "The percentage of hypertension patients receiving a diuretic rose to around 40 percent in the year after the Allhat results were announced, up from 30 to 35 percent beforehand, according to some studies. But use of diuretics has since stayed at that plateau. And over all, use of newer hypertension drugs has grown faster than the use of diuretics since 2002, according to Medco Health Solutions, a pharmacy benefits manger."
Why did this happen?
In the trial, patients taking Pfizer's Cardura were nearly twice as likely to require hospitalization for heart failure as those taking the diuretic. Pat;ients taking Norvasc, the calcium channel blocker from Pfizer in the Allhat trial had a 38 percent greater incidence of heart failure than those on the diuretic.
Those receiving the ACE inhibitor from AstraZeneca had a 15 percent higher risk of strokes and 19 percent higher risk factor of heart failure.
As Mr. Pollack went on to state: "Moreover, the diuretic cost only about $25 a year, compared with $250 for an ACE inhibitor, and $500 for a calcium channel blocker. So the diuretic was declared the winner."
(12/1/08)- Can statins lower the odds of death from pneumonia? The results of a Danish study that appeared in the October 27 edition of The Archives of Internal Medicine indicated that is so.
The scientists examined medical records of 29,000 Danish patients hospitalized for pneumonia over a six-year period of time. They examined the records of 1,372 of the patients admitted to hospitals with pneumonia who filled prescriptions for statins for a 4-month period of time prior to admission. Then they calculated mortality rates for statin users and nonusers.
After controlling for age, sex, heart disease, stroke, pulmonary illness, diabetes and 15 other disorders, they found that among statin users the odds of death were reduced by 31 percent within the first 30 days after admission and 25 percent within 90-days.
An editorial published with the study suggests that the drugs modify the production of certain proteins that cause the inflammatory response of pneumonia. By lowering the production of these proteins, statins may reduce the number of bacteria that can gain entry into cells.
The average age of statin users in the study was 73, and more than 60 percent were taking simvastatin, or Zocor.
(11/19/08)- As we stated in our item dated 11/7/08 below, the results of AstraZeneca PLC's Jupiter study of its cholesterol lowering drug Crestor were announced at the recent meeting of the American Heart Association meeting in New Orleans
The Jupiter study involved 17,802 participants who were entering prime heart attack ages, namely over 50 years of age for males and 60 years of age for females. None of the participants had evidence of serious heart disease or cholesterol levels high enough to be considered a problem.
The study found that Crestor reduced the risk of heart attacks, heart-related deaths and other serious heart problems by 44% compared with those given the placebo.
All participants did have elevated levels in their blood of C-reactive protein. Since over half of the victims of heart attacks in this country did not have high cholesterol levels there are many medical professionals who believe that cholesterol level is not the key factor in determining who is vulnerable to having a heart problem.
High-sensitivity CRP tests are available, and many insurance companies do cover this test. Just as the medical profession is not certain that high cholesterol levels lead to heart problems, they are not sure that high C-reactive protein levels are sure to cause heart attacks.
In the Jupiter study of 17,602 people who were divided into two double blind groupings (one group getting Crestor, the other group getting a placebo) the number of patients helped was small. Only 142 of the participants who received Crestor had major heart events, while 251 of those on the placebo did have major heart events.
Dr. Paul M. Ridker, director of the Center for Cardiovascular Disease Prevention at Brigham and Women's Hospital in Boston, and lead author of the study, stated that expanded use of statins could save over 250,000 lives over a five-year period of time.
Please keep in mind that AstraZeneca, the company that sells Crestor, funded the study. Crestor is the most potent statin on the market, and there are negative side effects that have been associated with the drug, including kidney problems and muscle deterioration.
Also please keep in mind that Dr. Ridker is a co-inventor of a CRP test, who stated that he had originally sought funding for this study from the federal government, but had been turned down by them.
In 2005 the FDA rejected a petition from the Public Citizen group to ban Crestor because the agency felt that the drug had no greater risk than did any of the other statin drugs.
(11/7/08)- The results of AstraZeneca PLC's study, known as Jupiter, of its statin drug Crestor will be made public on Sunday in New Orleans at the American Heart Association's annual meeting. The study was halted last spring, much earlier than expected, after a planned interim check found substantial reductions in death, heart attacks and other serious events among the subjects taking the drug compared with a placebo. There were 17,802 patients involved in the study group.
Patients involved in the study had "normal" levels of LDL, or bad cholesterol, and no evidence of heart disease. The patients did however have heightened levels of a marker for inflammation called C-reactive protein. Other studies have indicated that individuals with high levels of CRP are much more prone to have coronary events.
For more on this topic we have extracted an item dated 4/7/04 from Part I of the series in our earlier article on this topic:
"(4/7/04)- As a follow up to our item about the C-reactive protein (CRP) blood test in this article several weeks ago, the Centers for Disease Control and the American Heart Association has issued guidelines for the usage of this test. The test is not a replacement for traditional cholesterol and blood pressure tests. It should be used for patients whose risk already appears to be high from these other tests.
The guidelines are as follows: a reading below 1.0 is low risk, 1.0 to 3.0 is moderate risk, and over 3.0 indicates high risk. A report from the University of Cambridge in the United Kingdom was based on an 18,560 patient heart study in Iceland. It found that C-reactive protein did indeed predict heart attack risk independent of other factors. It did find however that the predictive finding was lower than earlier studies had shown. This study used 2.0 as the level for high risk instead of the 3.0 level as called for by the guidelines.
The FDA had previously approved the high sensitivity C-reactive protein (CRP) blood test, which costs about $20 to $50, for those who are at high risk of having a heart attack. Incidentally over one-half of the people who have heart attacks exercise regularly, don't smoke and have normal blood pressure and cholesterol levels. Insurance does cover the test for those who are at high risk of having a heart attack.
There are many physicians who believe that inflammation in the arteries cause heart attacks. The inflammation can lead to formation of plaque, hidden inside the artery walls. Levels of CRP rise when there is an inflammation, so elevated levels may indicate that there is a problem. Studies show that people with the highest CRP levels have a three to six times greater risk of heart attacks compared with those who have the lowest levels.
Researchers led by Dr. Paul M. Ridker, director of the center for cardiovascular disease prevention at Brigham and Women's Hospital in Boston concluded that women with high C-reactive protein were twice as likely to have a heart attack or stroke as women with high cholesterol. The CRP test was performed on President Bush when he had his annual exam in August. His level was low. About 650,000 Americans will suffer their first heart attack this year.
Most medical professionals consider the global risk score the most reliable tool for estimating the risk of a heart attack. The score is derived from a point-based formula derived from a combination of age, cholesterol level, blood pressure, whether or not the subject has been a smoker, and if the subject has diabetes. The score arose from the Framingham Heart Study, which has tracked the development and progression of heart disease in residents of Framingham, Mass. for the last 50 years.
The main problem with the CRP test is that there is no definitive answer as to what course patients and doctors should follow after seeing the results of the test. As we go on to show in this article, which type of treatment is best for a potential heart attack victim?
The protein is measured in milligrams per liter of blood and the lower the level the better. A high level is a reading of over 4.0. The measures already approved to treat and/or prevent heart attacks also lower the level of protein. These include exercise, weight loss, aspirin, smoking cessation and the use of the statin drugs. According to Dr. Robert Bonow, president of the American Heart Association, the association and Centers for Disease Control and Prevention will meet shortly to issue guidelines on this matter.
The researchers in the Ridker study measured levels of C-reactive protein and LDL cholesterol. They concluded that compared with high cholesterol, high protein was linked to about twice the risk of stroke, coronary disease or cardiovascular death. Their report was based on analysis of blood samples from nearly 28,000 participants in the Women's Health Study.
AstraZeneca PLC announced that Dr. Ridker would conduct a 3 1/2-year study, which will involve 15,000 patients to see if their statin drug Crestor can cut the risk of serious heart problems among patients with high levels of C-reactive protein. The trial will enroll male patients over the age of 55 and women over 65 who have LDL cholesterol under 130 and a C-reactive protein score over two, which indicates a moderate to high risk. Half of the patients will get 20-mgs a day of Crestor, which is known generically as rosuvastatin. The other half will get a placebo. The drug has not been approved for marketing yet in the U.S.
Although Bristol-Myers Squibb's "Prove-It" study seemed to have backfired on its cholesterol-lowering drug Pravachol, it does not seem to have effected sales of the drug according to the earliest data from ImpactRx Inc., a Mount Laurel, N.J., market research firm. The data garnered on a weekly trailing 7-day basis of a network of physicians shows that Pfizer's Lipitor upped its new prescription sales numbers from 27% as of March 4, to 40% as of March 18, the numbers for Pravachol remained about the same. On the other hand AstraZeneca's Crestor seemed to be effected the most, since new prescriptions for this drug fell to 17% from 28% as of March 4.
Since Crestor is more effective than Lipitor in lowering LDL, many analysts and physicians thought that Crestor would be a beneficiary of the study also. Some experts attributed the decline in the usage of Crestor to the fact that the advocacy group Public Citizens issued a call to the FDA to withdraw its approval of the drug because of potentially life threatening side effects. "Crestor is a very strong drug, but doesn't have much hard data to go for it, " said George Dangas, a cardiologist at the Lenox Hill Heart and Vascular Institute."
Dr.Paul Ridker, a Harvard cardiologist at Brigham, who headed the study that we discussed above, estimates that about 30 million Americans have high CRP levels and are therefore more subject to having coronary events.
We also discuss the CRP matter in our item dated 4/8/08 below.
(8/11/08)- The FDA warned doctors to use extra care when prescribing Zocor, generic Zocor, or Vytorin to patients who are taking amiodarone, a heart rhythm medication marketed as Cordarone or Paperone. The danger is highest for patients taking dosages of 20-mgs or higher.
Muscle injury is a risk for any patients taking any of the statin drugs for their high levels of cholesterol, particularly the elderly. The risk of this type of injury is very low overall, but it can be very serious because it can lead to kidney failure and even death.
The heart medication is mainly used to treat irregular rhythms in the ventricles, the heart chambers that pump blood to the lungs and body..
A previous warning dating back to 2002 about the drug's interaction apparently has not put an end to the problem, since the FDA said it had received 52 reports of serious muscle injury to patients taking the combination of medications, and almost all the patients had to be hospitalized.
(8/6/08)- The Enhance clinical trial was a 2-year study evaluating whether Merck's statin drug Zocor (80mgs) which when combined with Schering-Plough's Zetia (10mgs) to form the drug Vytorin was more effective in reducing atherosclerosis than was Zocor when taken alone. We discussed the Enhance study and the failure of Vytorin to reduce atherosclerosis any better than if Zocor was used as the sole drug in our item dated 1/26/08 and 1/22/08 below.
Now the data from the results of the SEAS clinical trial show that Vytorin does not decrease the chance of additional heart problems for those with stenosis, or a buildup of fatty tissue on the aortic valve. In fact, there were some indications that the patients in the SEAS trial had an increased risk of cancer, as opposed to those patients who were on the placebo.
The increased risk for cancer was very slight, and since the types of cancer that occurred were quite varied, there is a controversy that the drug does in fact increase the risk of cancer for patients who take it. A review of two other much larger trials did not find a similar risk.
Vytorin continues to be one of the best selling drugs in the world with over $5 billion in sales last year.
The SEAS trial involved nearly 1,900 patients whose heart valves were partially blocked. Scientists hoped that the trial would show that patients taking Vytorin would have a lower risk of need valve replacement surgery of having heart failure. The drug did not show those benefits.
To evaluate the cancer finding, Richard Peto, professor of medical statistics and epidemiology at the University of Oxford, examined the interim results of two other clinical trials of Vytorin, called Sharp and Improve-It.
The University of Oxford is leading the Sharp trial, which is sponsored by Merck and Schering but run independently by the university's Clinical Trial Service Unit.
The Improve-It trial is being led by investigators from Harvard and Duke University
Both Sharp and Improve It trials are comparing Vytorin with simvastin (Zocor) alone. Neither trial has yet been completed, but the two trials combined have about 20,000 patients. Mr. Peto stated, that so far, the number of patients taking Vytorin in the Sharp and Improve-It trials are at about the same level as those taking simvastin alone. "I think we should not be diverted by fears of cancer, " he said.
The primary researcher for the SEAS trial is Dr. Terje Pedersen of Ulleval University Hospital in Oslo, Norway. Vytorin did lower bad LDL cholesterol levels by 61% for those patients taking the drug in the trial.
Zocor is a statin drug that interferes with the production of cholesterol in the liver. A large body of research shows that statins reduce risk of heart attacks and strokes, but no such data exists to support use of Zetia, which blocks the absorption of cholesterol from the gut.
(5/26/08)- Merck & Co. announced that the company had halted its study of its prospective new cholesterol fighting drug MK-0524A, which is also known as Cordaptive. This is the drug that the company hoped would be the next generation of its cholesteral fighting drugs, but a steering committee of the company voted on May 14th to end the study.
For more on this topic please see our item dated 5/7/08 below. This vote to discontinue the study came only two months after that same steering committee voted to have more patients enrolled in the study.
The halted study, called Achieve, used ultrasound imaging to monitor plaque buildup in arteries of people whose genes give them high cholesterol levels. Several health professionals called upon the company to announce the reason why the study was being discontinued.
(5/7/08)- The FDA issued a "non-approval" letter, stating it needed more data on Merck's cholesterol lowering drug Cordaptive before it could give the okay on the drug. The agency also rejected Cordaptive as a brand name, so the company said it might use the name Tredative in the United States. On the other hand, a European Union advisory panel recommended approval of the drug for sale in Europe.
Merck has claimed that Cordaptive, which is also known as MK-0524A can both lower bad cholesterol levels (LDL) and raise good cholesterol levels (HDL).
The drug combines an extended-release form of B vitamin niacin, with a new agent, laropiprant, to inhibit a niacin side effect called flushing-redness, burning and tingling of the face. Niacin has been used to control cholesterol for decades, and an extended-release version called Niaspan, made by Abbott Laboratories has been on sale for years.
The results of a 24-week study of Cordaptive were reported on at a European cardiology conference in the fall of 2007. In that study researchers found that compared with a placebo, Cordaptive produced an 18% decline in levels of LDL cholesterol and a 20% increase in HDL levels. It also produced a beneficial 26% decline in triglyceride levels.
Laropiprant has drawn warnings from some health experts because of its possible link to blood clots, and because it has not been tested widely enough to be determined that it is safe.
The U.S. Patent Office has issued another preliminary rejection of Pfizer Inc.'s request for the reissue of a patent for its best selling cholesterol-lowering drug Lipitor. Lipitor's patent remains in effect until March 2010, but the company had hoped to have another patent for the drug reissued for another 15 months past that date.
(4/20/08)- Statins and Coronary Heart Disease- A meta-analysis of 9 randomized placebo-controlled studies of 19,569 patients looked at the effects of statins on mortality in elderly patients (aged >65) with documented coronary heart disease (CHD). They found that all-cause mortality was lower in patients treated with statins (15.6% vs 18.7%) with an estimated 22% reduction in relative risk over 5 years. Statins also reduced the risk of mortality from CHD by 30%, the risk of non fatal MI by 26%, the need for revascualrization by 30%, and the risk of stroke by 25%. It was determine that a median of 28 patients would need to be treated to save one patient. The authors concluded: "Statins reduce all-cause mortality in elderly patients and the magnitude of the effect is substantially larger than had been previously estimated. (See: Afilato J., Duque G., Steele R. et al. Statins for secondary prevention in elderly patients. A hierarchical Baysian meta-analysis. J Am Coll Cardiology 2008; 51(1):37-45)
(4/8/08)- AstraZeneca PLC announced that it stopped a clinical study of its blockbuster statin drug Crestor early, because the cholesterol-lowering drug showed clear benefits over a placebo.
The study was designed to determine whether the drug could reduce the risk of major cardiovascular events in patients with no symptoms of pre-existing cardiovascular disease and low cholesterol, but with high levels of a certain protein linked to heart problems (C-reactive protein).
(2/16/08)- Researchers continue to conclude that aspirin may help reduce the risk of colon cancer, when taken in large doses over a long period of time. Dr. Andrew T. Chan, an assistant professor of medicine at Harvard who led a study of 47,000 men over an 18 year period of time concluded: "The results provide additional proof that a simple drug like aspirin can help prevent colon cancer".
The results of the study that appeared in the January issue of Gastroenterology was not a randomized study, but some other randomized studies came to the same conclusion.
After adjusting for age, smoking, diet, physical activity and other risk factors, the researchers found that men who took more than two standard 325 mg aspirins a week reduced their risk for colon cancer by about 21% compared with those who took less. Men who took 6 to 14 tablets a week reduced their risk by 28%, and those who took more than 14 pills a week had a 70% decreased risk.
The longer the men took aspirin the more they reduced the risk, but taking it for less than five years, or taking the equivalent of less than one and a half pills a week, conferred no advantage. Other non-steroidal anti-inflammatory medications like ibuprofen (Motrin) and naproxen (Aleve gave similar protections, but not acetaminophen (Tylenol).
The negative side effects of taking aspirin range from upset stomach to gastrointestinal bleeding.
(2/1/08)- The cover story of a recent edition of Business Week casts a doubt on the benefits of statin drugs for non-high risk heart patients. In a study of non-high-risk patients, Pfizer Inc.'s Lipitor, for example, reduced the rate of heart attacks in a three-and-one-half year period of time to 2% from 3%. This means that to prevent one heart attack, 100 people had to take Lipitor for more than 3 years.
Pfizer reiterated that statins do reduce the "risk of death from coronary events", and proponents of statins say the impact needs to be calculated over a much longer period of time.
The magazine does concede however that: "If millions of people are taking statins, even the small benefit…would mean thousands of heart attacks are prevented."
Statins, like Lipitor and Zocor reduce the amount of cholesterol produced by the liver. Some studies have shown that statins greatly reduce the risk of heart attack in high-risk patients. They also do reduce the risk of inflammation. The negative side effect of statins is that they do cause muscle pain in some patients and can have negative effects on the liver.
Zetia has a smaller anti-LDL (bad cholesterol level) effect, and little effect on HDL, or inflammation, but since it works in the digestive tract, it potentially has fewer side effects.
Vytorin by combining Zocor (statin drug) and Zetia produces a bigger drop in cholesterol levels than either drug could do if it was working alone, and without a marked increase in side effects.
(1/26/08)- The ramifications of the Vytorin/Zetia controversy that we discussed in our item dated 1/22/08 below continue to swirl and expand, so that now an issue of conflict of interest has now entered into the plot. The Enhance end-point study of Vytorin, which is made as a joint venture between Merck & Co. and Schering-Plough determined that it was no better than the statin drug Zocor (also made by Merck) working alone at reducing arterial plaque.
The issue that initially caused consternation was the delayed release of the results of the study.
On January 15th, the day after the results of the study was released, the American Heart Association came out with a statement saying that the announced result was too limited to draw conclusions about Vytorin's ability to reduce heart attacks or deaths compared to Zocor alone. The association advised patients to consult with their physicians before discontinuing usage of the drug.
At no time did the association reveal that it receives nearly $2 million a year from the joint venture
Merck and Schering-Plough have suspended all television ads for Vytorin and Zetia, but print ads, defending the drug have been appearing as full page ads in newspapers such as the NY Times and the Wall St. Journal. .
Total U.S. prescriptions written for Vytorin in the week ended January 18th fell about 9.5% to 359,659 from 397,533 in the week ended January 11th, according to Verispan, a Yardley, Pa., drug-data firm. Prescriptions for Zetia, which the Merck/Schering-Plough joint venture also markets, fell 12% to 258,619 from 294,405 the week before according to Verispan.
(1/22/08)- The theory that lowering bad cholesterol levels (LDLs) is beneficial has been an accepted fact for decades now. The results of the Enhance clinical trial of Merck and Schering's combined drug Vytorin, and the disappointing results of the Illuminate study for Pfizer's drug torcetrapib (increasing the good HDLs drug) may be bringing into question that whole theory. For more on the abandonment of pursuing its selling of torcetrapib, please see our article dated 12/19/06 below.
The Enhance clinical trial was a 2-year study evaluating whether Merck's statin drug Zocor (80mgs) which when combined with Schering-Plough's Zetia (10mgs) to form the drug Vytorin was more effective in reducing atherosclerosis than was Zocor when taken alone.
The results of the study as released by Merck and Schering-Plough showed that the study failed to meet the primary as well as the secondary end points. As a matter of fact not only did Zetia fail to slow the accumulation of fatty plaque in the arteries, it actually seemed to contribute to plaque formation, although by such a small amount that the finding could have been a result of chance.
Dr.Steven E. Nissen, the chairman of cardiology at the Cleveland Clinic said, "This is as bad a result for the drug as anybody could have feared." Dr. Eric J. Topol, a cardiologist and director of the Scripps Translational Science Institute in La Jolla, Calif said, "The idea that you're just going to lower LDL and people are going to get better, that's too simplistic, much too simplistic."
The Enhance trial covered 720 patients and lasted two years. It was completed in April 2006. In November 2007, the companies announced plans to change the trial's primary measure of effectiveness to "expedite their analysis", but they reversed course last month after a large outcry of criticism about the ethical matter in changing the primary measure of a trial.
Merck and Schering recently began a large study intended to test whether the combination of Zeia and statin drugs actually reduces heart attacks and strokes when compared with statins alone. The study involves doctors at Harvard and Duke Universities and is called Impove-It, but it will not be available until at least 2011.
Because the link between excessive LDL cholesterol levels and cardiovascular disease has been so widely accepted, the FDA generally has not required drug companies to prove that cholesterol medicines actually reduce heart attacks before approval.
They have not had to conduct so-called outcome or event trials beforehand, which are expensive studies that involve thousands of patients and track whether episodes like heart attacks are reduced.
We are reprinting our article on the Enhance study, which was intended to prove the value of Vytorin which appeared in our article Release of Clinical Drug Trial Data
(12/27/07)- Partial results of studies that had been conducted by Merck and Schering-Plough, showed the possibility that Schering-Plough's cholesterol medication Zetia, when combined with statin drugs might cause damage to the liver, and that this risk had not been revealed by the companies. The discovery of the unpublished research adds more fuel to the controversy involved in the failure of Schering and Merck to make a timely disclosure of the results of the Enhance study that we discuss in the items below.
A Schering executive, Dr. Robert J. Spiegel, when queried about the unpublished studies confirmed their existence. Dr. Spiegel went on to explain that Merck and Schering did not consider the studies scientifically important enough to publish the findings.
Before Zetia was approved in 2002, one FDA reviewer said it should not be cleared for use with statins, because the combination had caused liver damage in animals. In the last two years, scattered case reports of severe liver damage in patients taking Zetia in combination with statins have appeared in medical journals.
The label for Zetia contains only mild warnings about the drug's potential for liver damage. Regulators in Australia and Canada have warned since 2005 about the drug's potential to cause hepatitis, pancreatitis and depression. Most of the studies for which Merck and Schering have published results for Zetia covering only 12 weeks, which is not enough time for liver problems to develop in most patients.
The unpublished studies were conducted from 2000 to 2003 according to FDA documents but were not listed on the industry Web sites where campaniles are supposed to register the results of all drug trials that were ongoing after October 2002. When the FDA approved Zetia in 2002 it relied on trials that covered only 3,900 patients and lasted no more than 12 weeks.
The data from those trials indicated that Zetia might be dangerous when it is combined with a statin.
Reversing course once again, Merck & Co., and Schering-Plough announced that they would present the full results of the Enhance study at the American College of Cardiology's conference in Chicago in March 2008. Please see our items on this topic dated 12/19/07 and 12/4/07 below.
The lead researcher for the study, Dr. John P.Kastelein, a cardiologist at the Academic Medical Center, said that he regretted not standing up to the companies when they announced on November 19 that they would announce only limited primary endpoints for the study, and not the full primary endpoints. The study was completed in April 2006.
The Enhance study was intended to determine whether the combination treatment of Schering's Zetia and Merck's Zocor works better than Zocor alone. Vytorin is a combination pill of both Zetia and Zocor. Zetia is not a statin drug. The study was initially designed to measure changes in the thickness of the carotid artery walls after two years of treatment.
That measurement was taken at 6 points-3 different locations- in carotid artery and would serve as the primary endpoint of the study.
(12/19/07)- The House Committee on Energy and Commerce Chairman John D.Dingell (Dem.-Mich.) and Bart Stupak, the chairman of the committee's subcommittee on oversight and investigations sent a letter to Merck and Schering Plough regarding that "we are concerned with the delay in releasing the results of the study (Enhanced)" that we discuss in our item dated 12/4/07 below.
Vytorin accounts for more than 50% of Schering-Plough's earnings per share, and about 20% of Merck's earnings per share. As we note in the item below the companies completed the study in early 2006 of the drug, and announced that they would reveal the results of the study in 2007. On November 16th they announced that after consulting with an independent panel of clinical biostatistical experts, that they had decided to change the primary endpoint of the ENHANCE trial. It is very unusual to change the endpoint of a study.
(12/4//07)- Nearly two years after the completion of a clinical study of the cholesterol lowering drugs Zetia and Vytorin in combination, the results have still not been published. Even though there are 800,000 prescriptions written each week, at a cost of about $4 billion, the results of the trial, called Enhance are still unknown.
The two drug manufacturers of the drugs recently announced that they would release the results of one of the three original end-points of the study in March 2008 at the American College of Cardiology's conference in Chicago. The results of a larger clinical study of the drugs are not due to be released until at least the year 2010.
The companies originally said that they would measure the thickness of plaque in two arteries. The first artery would be the carotid artery, which runs through the neck and supplies the brain with blood. The second artery would be the femoral, which runs through the hips and supplies blood to the legs. The primary endpoint of the study was supposed to be the amount of plaque at three points in the carotid artery.
The companies announced however that they would announce only the endpoint of the study at the meeting to releasing only the measurement of the thickness at just one point in the carotid artery. At the same time they announced that they do not expect to release any results from the femoral artery study.
Dr. John Kastelein, a Dutch cardiologist who oversaw the study stated that he believed that the trial should still be considered valid.
The Enhance trial was supposed to show that Zetia and Vytorin (simvastatin) when used together would reduce the growth of plaque in blood vessel walls more than if simvastatin were used alone.
Zetitia works differently than does the statin medications such as Prizer's Lipitor or Merck's Zocor. The FDA approved Zetia in 2002 on the basis of trials that showed it could lower LDL, or so-called bad cholesterol, by 15% to 20%. It is the brand name medication for a cholesterol-lowering medication known as ezetimibe.
It can be taken with any of the statin medications. Vytorin is a pill that combines Zetia with simvastatin, the active ingredient in Merck's Zocor medication. Zetia and Vytorin both cost about $3 a day.
Dr. Eric J. Topol, a cardiologist and director of the Scripps Transitional Science Institute in La Jolla, California stated: " There has yet to be a clinical trial to show that ezetimibe improves clinical outcomes."
(1/19/08)- Genzyme Corp., a biotechnology company based in Cambridge, Mass., has agreed to pay at least $325 million to Isis Pharmaceuticals Inc., of Carlsbad, Ca., for the rights to its potentially powerful cholesterol lowering drug, mipomersen, that Isis is developing.
Mipomersen is in the last stage of clinical trials as a treatment for a rare genetic disease that causes people to have astronomical cholesterol levels. There are only about 10,000 people in the world with the most severe form of the disease, which can cause heart attacks even in young children.
The drug lowered levels of cholesterol and other blood lipids more than 40% beyond reductions achieved by statins and other existing drugs alone, according to Isis.
Stanley T. Crooke, the chief executive of Isis, said that because mipomersen is injected once a week, it would be aimed at supplementing statins, not competing with them. "It's not going to replace statins, and we would never dream of replacing statins," he said.
Isis expects to file for FDA approval of the drug next year. If approved, mipomersen would likely come on the market in 2010 or 2011.
(9/19/07)- Why are men more reluctant than women to call for an ambulance when they are having a heart attack? In a recent study that was conducted in Minnesota of 1,263 patients who suffered a heart attack, it was found that only 37% of the men in rural areas called for an ambulance while 49% of the women arrived at the hospital in an ambulance.
As a matter of fact the studies have shown that only about half of the people in the throes of a heart attack call for an ambulance. Even calling your personal physician leads to what often may mean fatal delays.
Up to 5% of patients go into cardiac arrest en route to the hospital. If you are not revived within two minutes of cardiac arrest the odds for survival plummet dramatically.
The results of the Minnesota study were presented by Minneapolis Heart Institute researchers at a meeting of the Society of Academic Emergency Medicine last May. The study concluded that patients from rural areas were treated 6 minutes sooner if they called 911, and patients from urban areas were treated, on average, 18 minutes faster when they called an ambulance.
(6/19/07)- The results of a statistical analysis that was done by the Centers for Disease Control and Prevention in Atlanta determined that the rate of death in the U.S. from heart disease was cut in half between 1980 and 2000. The analysis showed that better medication and a reduction in incidence of some risk factors was the main reason for the improved results.
About 47% of the reduction resulted from medical measures such as drug to reduce cholesterol and blood pressure, land improved medical treatment in general. Another 44% of the reduction in deaths came from lifestyle improvements, such as less smoking, healthier dieting and increased exercise.
Janet Croft of the CDC was the lead researcher for the analysis, the results of which were published in a recent edition of the New England Journal of Medicine.
(5/2/07)- Ranbaxy Pharmaceutical Inc., a wholly owned subsidiary of Ranbaxy Laboratories Ltd. of India announced on April 25th that it had received approval from the FDA to manufacture and market Pravastatin Sodium Tablets in 10mg, 20mg, 40 mg and 80 mg doses. The company will have 180- day exclusivity to market the 80 mg dosage in the U.S.
The Office of Generic Drugs, of the U.S. FDA has determined that their formulation is the bio-equivalent and, therefore, therapeutically equivalent to the reference listed drug Pravachol.
Pravachol is manufactured by Bristol Myers Squibb, and it had over $1.9 billion in sales last year. The drug is used to try and help prevent coronary events.
(4/11/07)- The U.S. Supreme Court declined to intervene in Ranbaxy Laboratories Ltd's appeal of a lower court ruling upholding Pfizer's patent for Lipitor, the top selling cholesterol lowering drug. Ranbaxy is the Indian generic drug company that sought to make a generic version of the drug.
Although consumers are able to purchase a generic version of Merck &Co.'s cholesterol lowering drug Zocor, a recent ruling by the U.S. Court of Appeals will mean that Pfizer's cholesterol lowering drug Lipitor is safe until 2010 from having a generic version of their drug. Lipitor was the world's best selling drug last year garnering over $14 billion in sales in 2006. Both Zocor and Lipitor are in a category of drugs known as statins.
Even though a generic version of the cholesterol-lowering drug became available in the 3rd quarter of 2006, it could not prevent Pfizer's marketing machine from continuing to increase sales of Lipitor.
The U.S. Court of Appeals for the Federal Circuit refused to reconsider a lower court August 2 decision that upheld one of Pfizer's Lipitor patent's, while invalidating a 2nd patent that was due to expire in 2011.
(3/29/07)- AstraZeneca PLC of England and AtheroGenics of Alpharetta, Ga., co-marketers of AGI-1067, a new experimental drug aimed at reducing the buildup of plaque inside arteries announced that the drug did not meet its Phase III trial expectations.
The drug was no more effective in reducing the risk of death in a trial involving 6,127 high-risk patients than was the placebo. The drug was the first of a new class of medications called vascular protections, which work by blocking the inflammatory process in arteriosclerosis. Arteriosclerosis is the buildup of plaque, fat, cholesterol and other substances in the inner lining of an artery.
Patients in the trial all had a history of heart disease and all were being treated with a variety of other heart medications, including cholesterol-lowering statins.
AGI-1067 is a drug with both anti-inflammatory and antioxidant activity. AstraZeneca's Crestor has become one of the leading statin drugs in the battle against heart disease. In October 2006 the company discontinued testing of its stroke treatment drug NXY-059.
(3/11/07)- The FDA has granted approval to Novartis AG, the Swiss drug company to sell its blood-pressure medication Tekturna, which is generically known as aliskiren. This is the first new type of medication for treating high-blood pressure approved in more than a decade.
It was developed in collaboration with Speedel Holding AG, a small Swiss pharmaceutical company that was founded by a former executive of Novartis, Alice Huxley. Novartis had the original rights to develop the drug, but after having run into snags in developing the drug, turned to Speedel for further work on the medication.
After Speedel managed to simplify the drug's chemical synthesis, Novartis bought back the rights to the drug and completed its development. Novartis submitted Tekturna for European Union approval in September 2006. If approved it would be sold under the brand name of Rasilez in Europe.
(3/5/07)- The results of a recent 6 month study of 192 adults with mildly elevated cholesterol levels showed that there is no evidence to support the theory that garlic works any better than a placebo in reducing blood lipid concentrations.
The results of the study appeared in a recent edition of The Archives of Internal Medicine.
Researchers divided the participants into four groups to consume either raw garlic, a powdered garlic supplement called Garlicin, a popular brand of aged powdered garlic called Kyolic 100 or a placebo.
The doses were the equivalent of one four-gram clove of garlic a day, six days a week for six months.
The researchers tested for LDL cholesterol, HDL cholesterol, triglycerides and total cholesterol HDL ratio, but found no statistically or clinically significant difference between garlic users and those who received the placebo. Christopher D. Gardener, who is an assistant professor of medicine at Stanford University, was the lead author of the study.
(2/9/07)- Back in 1975 a study of 8,341 subjects who had suffered heart attacks found that niacin, or vitamin B, was the only treatment among five tested that helped to reduce the risk of a second heart attack. Compared with men on placebos, those on niacin had a 26% reduction in heart attacks and a 27% reduction in strokes. Fifteen years later, the mortality rate among the men on niacin was 11% lower than among those who had received the placebos.
The reason advanced for this difference is the fact that niacin improves the HDL, or good cholesterol level. It is estimated that niacin can improve the HDL level by as much as 35% when taken in high dosages of about 2,000 mgs a day. It also lowers the LDL level, or bad cholesterol level, but not as much as the statin drugs do.
Niacin has also been shown to reduce serum levels of artery-clogging triglycerides as much as 50%. On the down side is that it dilates the blood vessels and causes flushing problems. In rare cases the vitamin can cause liver damage and can impair the body's use of glucose. High doses should be taken only under the strict supervision of a physician.
Researchers at 72 sites in the U.S. and Canada are recruiting 3,300 heart patients for a study led by Dr. B. Greg Brown, professor of medicine at the University of Washington in Seattle which will compares those who take niacin and a statin with those who take only a statin. The National Institutes of Health will finance the study.
Doctors who do recommend niacin for their patients recommend that it be started on small dosages, and also that food be eaten at the same time as taking the pill. A new Merck drug is being tested in Britain to counteract the niacin-induced flushing problem. If it works, the company plans to bundle the drug with its own extended-release niacin and Zocor, its statin drug that came off patent recently.
(12/26/06)- According to the results of research by scientists from the Framingham Heart Study, the new blood tests being administered now are no more accurate at predicting who will get a heart attack than are the old measurements of cholesterol level, blood pressure, and other conventional measurements
These substances included C-reactive protein, or CRP; homocysteine; and BNP, or B-type natriuretic peptide. The difference in accuracy of these new tests was considered so small as to be negligible. "It's a little bit disappointing," said lead author Thomas J. Wang, a Harvard Medical School assistant professor.
The results of the study were published recently in the New England Journal of Medicine. The researchers used frozen blood samples taken from 3,200 healthy Framinghma, Mass., participants in the mid-1990s, and then checked to see who had major heart complications or died over the following decade.
"This really supports the value of focusing on risk-factor reduction, not looking for a magic blood test, "said Richard Stein, director of preventive cardiology at Beth Israel Medical Center in New York
As a follow up to our item about the C-reactive protein (CRP) blood test in this article several weeks ago, the Centers for Disease Control and the American Heart Association have issued guidelines for the usage of this test. The test is not a replacement for traditional cholesterol and blood pressure tests. It should be used for patients whose risk already appears to be high from these other tests.
In the accompanying chart we list some of the risk factors, and the levels to consider for being at risk for a heart attack:
HDL (good cholesterol)
Body Mass Index
Key Levels to Watch
3mg/L or higher
200 mg/dL or higher
40/dL or lower
115/75 or higher
25 or higher
(12/19/06)- Cardiovascular conditions resulted in over 911,000 deaths in America in 2003.according to the American Heart Association. This made it the number one killer and unfortunately what was once a promising drug in the battle against the disease will now have to be discarded. The drug is Pfizer Inc.'s torcetrapib, which the company had expressed the hope would become a billion dollar seller in the next few years.
Torcetrapib works by increasing the good cholesterol level or HDLs. The failure of this drug in its trial study, which was called Illuminate, will result in the company's taking close to a billion dollars to write off. The trial had been scheduled to end in 2009.
Illuminate compared 7,500 patients taking a combination of torcetrapib and Lipitor, Pfizer's best selling statin drug, with a similar number of patients taking only Lipitor. The patients had diabetes or cardiovascular disease, making them higher risk candidates to having heart attacks or strokes.
Not only were there 31 more deaths among the people taking torcetrapib,, but similar discrepancies were seen in the number of patients suffering heart failure and other serious problems. Those patients taking torcetrapib saw a significant increase in their blood pressure levels also.
The question still remains open as to whether or not increasing the good cholesterol levels (HDL) is beneficial in preventing heart problems, or in the case of torcetrapib, is the problem of only this particular drug. AstraZeneca's Crestor increases the good HDL levels as well as reduces the bad LDL levels.
(12/4/06)- Isis Pharmaceuticals, which is based in Carlsbad, California said that preliminary results of the Phase II study of its cholesterol drug ISIS 301012 showed that the drug cut levels of "bad" cholesterol 62% for patients who received the drug over a 3 month period of time.
The results of the study were announced at the American Heart Association's annual meeting in Chicago recently. Patients who took the drug with statins, had 51% lower levels of "bad" cholesterol after 5 weeks than those who took statins alone.
(11/1/06)- How low should your harmful LDL cholesterol level count reach? Two years ago, the National Cholesterol Education Program urged high-risk patients to reduce their LDL levels to below 100 milligrams a deciliter, from the prior recommendation of 130 milligrams. Those who are considered at very high risk were recommended to get their LDL levels to less than 70 milligrams.
A recent study questions whether or not getting the cholesterol count to these lowered levels is effective in preventing heart attacks.
"This paper is not arguing that there is strong evidence against the LDL targets, but rather that there's no evidence for them," said Dr. Rodney A. Hayward, a study author. The study went on to question the methodology in which the clinical trials had been devised and carried out.
The results of this study were published in the October 3rd issue of Annals of Internal Medicine. Dr. Hayward is director of the Veterans Affairs Center of Health Services Research and Development, and a professor at the University of Michigan Medical School.
Statins have effects other than just lowering cholesterol levels, such as anti-clotting and anti-inflammatory results, that can be deemed harmful to a patient.
(8/30/06)- Merck & Co., the Whitehurst Station , N.J. pharmaceutical company, released the preliminary results of its large study called Medal of Arcoxia, the drug that the company hopes will replace Vioxx, the painkilling medication that it had to withdraw from the market in September, 2004.
Arcoxia is already approved to be sold in 62 countries, and garnered $126 million in sales in the first half of this year. At last count, Merck is faced with over 14,200 lawsuits as a result of Vioxx.
According to Merck, the preliminary results of the Medal study showed that Arcoxia is no more dangerous to the heart than is diclofenac, a prescription drug sold under brand names that include Cataflam and Voltaren. Diclofenac is not popular in this country because of fear that the drug increases liver problems.
Both Arcoxia and diclofenac belonhg to the class of drugs known as non-steroidal anti-inflammation drugs (Nsaids).
The company's statement also indicated some potential worries for Arcoxia, namely increased rates of hypertension and edema that caused some of the Arcoxia patients to drop out of the study.
There were three clinical studies done of a total of 34,700 patients in the Medal study. Patients took the drugs for an average of 17 months, and 10,000 of the patients took them for two years or more. The 17-month period of time is interesting, since many health professionals feel that Vioxx major problem for heart attacks arises after 18 months of usage of the drug.
On average, patients who took Arcoxia were slightly less likely to have a heart attack or other serious cardiovascular problems than those who took diclofenac, according to Merck.
Many health professionals feel that a more accurate measurement for Arcoxia would have been to compare it with naproxen-sold over the counter as Aleve- rather than diclofenac.
Both Arcoxia and diclofenac are Cox-2 inhibitors, as are Vioxx, and Celebrex, the Pfizer painkiller that is still on the market. In announcing the preliminary results Merck stated that it intended to push for FDA approval to sell the drug in this country.
In October 2004, the FDA responded to Merck's application for approval to sell Arcoxia by asking for more information.
(8/19/06)- The results of a recent study of Pfizer Inc.'s cholesterol-lowering medication Lipitor that was published in the latest edition of the New England Journal of Medicine found that the drug had only modest success in lowering the stroke rate in people with prior strokes.
Although the study showed that Lipitor did have a slight affect in lowering the risk of stroke for patients who had prior strokes, it did increase the risk for those having hemorrhagic strokes. Hemorrhagic or brain strokes are the more devastating type of stroke as opposed to the other type of stroke known as ischemic stroke, which is generally caused by a blood clot, or a mini stroke.
The study looked at 4,731 people who had no known cardiac problems but had experienced at least one stroke within the prior one to six months. Pfizer Inc sponsored the study.
Lipitor is approved for stroke prevention in people who have, or are at high risk for, coronary disease. Among the patients who took Lipitor, 265 or 11.2% suffered another stroke over a five-year period of time. That compared with 311, or 13.1%, or those getting placebo pills that suffered an additional stroke.
55 of the patients who were taking Lipitor suffered hemorrhagic strokes compared to only 33 of the patients taking the placebo who suffered strokes.
One of the study's co-authors, Justin A. Zivin of the University of California, San Diego said; "The (beneficial effect) is about what you get from aspirin. It's not dramatic or earth shattering."
Hemorrhagic strokes are rarer than ischemic strokes, accounting for less than 20% of the 700,000 strokes each year in the U.S., but they carry a much higher risk of long term disability, especially to people who are on blood thinners such as Coumadin.
(7/27/06)- Merck's Zocor, its cholesterol-lowering drug, which lost its patent in the U.S. on June 23 is having an effect on the sale of Pfizer's Lipitor and AstraZeneca's Crestor. It is also leading the other generic drug sellers of simvastatin, the generic name for the drug.
Merck's generic version of the drug captured 49% of new prescriptions in the U.S. for the drug that were written for the last week in June. Teva Pharmaceutical Industries Ltd of Israel captured 32% of the 236,000 new prescriptions for all dosages during the last week of June. Dr. Reddy's Laboratories of India, which makes generic simvastatin under an agreement with Merck gained 14% of the new prescription market for the drug, while Ranbaxy Laboratories Ltd of India, which makes only the highest dosage of the drug gained 3% of the market.
Sales of Lipitor, the most popular version of the statin drugs sold to combat high cholesterol levels saw its percentage of the market for the medication drop to 40% from 42% the week before when the generic version of the drug was not available.
According to data from ImpactRx, a research firm in Mount Laurel, N.J. Zocor and simvastatin sales combined prescriptions exceeded those of Lipitor for the first week in July among primary-care doctors. During the week ended July 7, Zocor and simvastatin accounted for 23% of cholesterol drugs prescribed for newly diagnosed patients or those switching medications, compared with 20% for Lipitor. Just a month earlier, Lipitor claimed 23% of new prescriptions while Zocor accounted for only 16% of the prescriptions.
(7/4/06)- A federal judge has denied a motion from Novartis AG to temporarily block the FDA from approving Teva's and Ranxbary's generic versions of Zocor, and affirmed their 6-month marketing exclusivity. Novartis' generic division Sandoz wanted to market a generic version of the drug, but Judge Royce C. Lamberth of the U.S. District Court for the District of Columbia said the temporary delay would be detrimental to both Teva and Ranxbary. He went on to say that even a temporary delay would be harmful to the public.
Teva won approval to market the pill in 5-, 10-, 20-, and 40-milligram versions, while Ranbaxy won approval to sell the 80-mg version of the drug. Dr. Reddy's Laboratories Ltd, under an agreement with Merck will be the so-called authorized generic maker of the pill and will sell all five dosages.
(6/25/06)- On June 20, 2006 the patent for Merck & Co.'s cholesterol-lowering drug Zocor expired. In a very interesting move, the company has sharply lowered the price of the drug, and is selling it as a branded generic version of simvastatin. By adopting this strategy of selling the generic version of the drug at a sharply lower price, Merck is hurting the generic drug companies Teva Pharmaceuticals USA, a unit of Teva Pharmaceutical Industries Ltd., of Israel and Dr. Reddy's Laboratories Ltd., an Indian generic drug maker.
These two generic drug companies are being hurt by this action since they expected to have the exclusive right to market the generic version of Zocor for the first 6 months after the patent expired. They were the two companies that were the first ones to apply to market the generic version of the drug after the patent expiration. The law dictates that the first applicants who receive the approval of the FDA to market the different dosages of the drug have the right of exclusivity of the 6-month period of time after the patent expires.
This article contains information about other instances of the pharmaceutical companies making "branded" generic versions of their drugs. In selling a branded version of a drug, whose patent has expired, a drug company can thus capture a portion of the sales after the patent's expiration. This in turn is harmful to the generic drug company that expected to have exclusive rights to sell the generic version of the drug for 6 months after the expiration.
It is reasonable to expect that many drug companies will adopt this strategy in the future when the patent expires on one of its drugs.
WellPoint Inc., an Indianopolis health insurer announced that it had entered into an arrangement with Merck to sell branded Zocor, and not competing generic versions, through its mail order pharmacy service. Members of WellPoint will pay $10 for a 30-day supply of branded generic Zocor.
UnitedHealth Group Inc. said that branded generic Zocor would move to the cheapest tier of its drug formulary, making the co-payment for customers cheaper than the generic alternatives.
Making a branded generic version of Zocor is going to have a huge impact on Pfizer's Lipitor, the biggest selling drug in the world, with revenues worldwide of $12 billion last year. On a personal basis, this author's pharmacy benefits manager ExpressScipts notified all members of its plan with the company I work for, that the co-pay for a 90-day supply of Lipitor would be increased from $70 to $140.
Lipitor is now faced with competition from two drugs that lower cholesterol even more than it does. One is Vytorin, which is made by Merck and Schering-Plough, which combines Zocor and Zetia. This combined pill has a different mechanism of action than statins. In addition to lowering the bad cholesterol level, the drug also increases the users good-cholesterol level. This drug had sales of $378 million in the first quarter, which indicates that it is on track to become a blockbuster over a billion dollar seller this year.
The other new challenger to Lipitor is Crestor, a drug from AstraZeneca that is generally considered the most potent of the statin drugs.
Up until now, Zocor has sold for about $3 per pill. Once it is sold as a generic drug, the price probably will go down between 75% to 90%. The falling price will save insurers and patients billions of dollars. It is unknown at this point if employers will benefit to any great amount by this action.
For more on this topic please see our article on "Branded" Prescription Drugs"
(6/12/06)- According to a recent research report that was published in The New England Journal of Medicine ACE inhibitors may cause birth defects if taken by pregnant women in the first three months or pregnancy. It had been previously determined that ACE inhibitors can cause birth defects if taken later on during pregnancy, and drug labels have the warning for pregnant women in the second and third trimester..
Pregnant women and those planning to become pregnant should avoid the drugs, according to the researchers and officials at the FDA. The researchers had studied the medical records of 29,507 infants. The study found 209 infants who had been exposed to the drugs in the first trimester. Of the 209, 18 had birth defects; in half of the 18 cases the heart of the newborn was affected.
Dr. Robert Temple, an associate director of the Center for Drug Evaluation and Research at the FDA, said the 2.7 fold increase in risk was "moderately large", but the agency does not plan to require a "black box" change in ACE inhibitors labeling information as of now. He said that further studies were needed before the warning need be placed on the prescription label.
ACE inhibitors are used to treat high blood pressure. Last year there were about 42 million prescriptions written for the drug. According to Dr. William O. Cooper, a Vanderbilt pediatrician who headed the study team, there were about 2.7 million ACE inhibitor prescriptions written for pregnant women in 2002
All drugs are tested in pregnant animals before they are marketed. It is obviously unethical to test these same drugs in pregnant women, so this risk factor can not be evaluated until after pregnant women have used a drug. With more and more women giving birth at later ages this will become an even more difficult problem for our society.
Some of the better selling ACE inhibitors are, Merck's Vasotec, Pfizer'sl Accupril and Bristol-Myers Squibb's Capoten.
A study published in 2002 found that diuretics were as effective in preventing heart attacks as ACE inhibitors.
(5/26/06)- A study that examined FDA records from the last ten years concluded that about 164,000 emergency defibrillators had been subject to FDA recall or alert notices. This works out to about one out of every five units that were sold during that period of time.
The study's lead author, Dr. William H. Maisel of Beth Israel Deaconess Medical Center in Boston said, "Many failure occurred during life-threatening circumstances." "It does not mean that every one of these people could have been saved, but these are very high risk malfunctions." The study did not address internal defibrillators, which are surgically implanted into the chests of heart patients who are at high risk of cardiac arrest
(3/26/06)- In a study of more than 500 patients who were taking a high dosage of AstraZeneca's statin drug Crestor the volume of plaque was reduced by 7% to 9%. The drug also lowered levels of LDL, or bad cholesterol, by more than 53%, and it raised levels of HDL, or good cholesterol by nearly 15%. The results of the study were presented at the recent meeting of the American College of Cardiology in Atlanta.
The issue remains however as to whether or not the lowering of the plaque level will mean fewer heart attacks and strokes. Artherosclersis, or blockage in arteries, results when a buildup of cholesterol, inflammatory cells, and fibrous tissue called plaques form in an artery wall. If these plaques break off, it cause blockages prevent the blood from flowing properly where needed by critical organs leading to heart attack or stroke.
All the statin drugs lower the level of plaque in arteries, although some do it to a greater extent than the others.
A consumer group, Public Citizen to have Crestor petitioned the FDA last year to ban Crestor as unsafe, but the agency denied the request.
Homocysteine level, an amino acid that many health professionals believed to be as important and dangerous a risk factor for heart disease and stroke was the subject of 3 studies that were reported on recently. It is also an accepted hypothesis that the B vitamins, namely: vitamin B12, vitamin B6, and foliic acid, could protect against high homocysteine levels, which in turn would mean less risk of heart attack or stroke.
The results of the three studies however showed that by decreasing the homocysteine level, the number of patients having cardiovascular problems did not decrease. There are no known harmful affects from taking the B vitamins.
All three studies showed that the vitamin regimens drove patients' homocysteine levels down by nearly one-third. All three studies however did not show any decrease in the amount of cardiovascular problems in the group receiving the vitamin B pills from those who only received a placebo.
"The evidence is clear that this type of vitamin therapy is really not effective in reversing or benefiting advanced vascular disease", said the hypothesis's father, Dr. Kilmer McCully of the V.A, Boston Health Care System in West Roxbury, Mass.
The Canadian Institutes of Health Research sponsored one of the studies. It involved 5,522 men and women 55 or older who had diabetes or had had a heart attack or had documented heart disease. The patients in this study were monitored for five years. The second of the studies involved 3,749 men and women ages 30 to 85 that had recently had a heart attack. It was known as the Norwegian Vitamin Trial, and it lasted for three years and four months.
The third study involved 3,680 stroke patients, some of whom were randomly
chosen to take the vitamins.
(3/21/06)- The anticlotting drug Plavix had over $6.2 billion in sales last year for its distributors Sanofi-Aventis SA of France and Bristol-Myers Squibb of New York. The drug has been approved for usage, along with aspirin, after a patient has had a heart attack, but the question has arisen if the drug would be useful in preventing heart attacks in individuals who are at high risk for having one. Plavix was the second most widely sold drug in the world last year, trailing only Pfizer's Lipitor in 2005.
The answer to this question seems to be no, based on the results of a study of 15,000 patients who were deemed to be at high risk for having a heart attack. These individuals were at high risk because they had had a stroke, or a blocked artery in the leg.
The drug, which is also known generically as clopidogrel, was found to be of no help in preventing a heart attack. The Plavix offered no benefit over standard low-dose aspirin therapy, and in fact it significantly increased the risk of internal bleeding. In fact, when combined with aspirin it was determined that there was only a 1-% reduction in the risk of heart attack.
The study, called Charisma, was presented at the annual scientific meeting of the American College of Cardiology in Atlanta. Both aspirin and Plavix inhibit platelets from forming clots. Researchers found that 6.8% of patients with the combination of Plavix and aspirin had either a heart attack or a stroke or died of cardiovascular disease-compared with 7.4% who were on aspirin plus placebo.
Among patients without established cardiovascular disease, the rate of death from cardiovascular causes was 3.9% for those taking Plavix and aspiriin, compared with 2.2% for those taking aspirin alone.
Plavix is approved for patients with a recent heart attack or unstable chest pain, and for people treated with drug eluting stents. Studies have shown that when such patients stop Plavix, even while continuing aspirin, they significantly increase the risk of developing a clot in the stent.
(1/12/06)- Researchers concluded, after analyzing 26 randomized studies
involving more than 73,000 patients, that statin drugs had no effect on cancer
risk or cancer deaths. The findings appeared in the recent issue of the Journal
of the American Medical Association. The results of the study therefore
contradicted the results of a non-randomized study that concluded that statins
did have the beneficial effect of lowering the risk of colorectal cancer in
people who used statins for at least 5 years.
In a separate study, the results of which appeared in the Journal of the National Cancer Institute, it was determined that the statins drugs had no effect in reducing the risk of colorectal cancer. This study looked at data on more than 132,000 people who enrolled in a cancer-prevention study.
C. Michael White of the University of Connecticut School of Pharmacy led the analysis of the data appearing in the Journal of the American Medical Association.
(12/20/05)- Judge Joseph J. Farnan Jr. of the Federal District Court in Delaware ruled that two critical patents protecting atorvastatin, the active ingredient n Lipitor, are valid. As a result of this ruling Pfizer's patent on Lipitor will hold until June 2011. Ranbaxy Laboratories, the Indian drug company will appeal the ruling. For background information on this case please see our article: Patents and Prescription Drugs -Part II and also Cox-2 Inhibitors and Rheumatoid Arthritis-Part III
(11/16/05)- According to the results of a study, that was published in the October 18 edition of Lancelot, beta-blockers do work to reduce the risk of stroke, but not as well as other medicines, and they are ineffective in preventing heart attacks. Dr. Lars H. Lindolm, the chairman of the department of public health and clinical medicine at Umea University Hospital in Sweden, and the lead author in the study stated: "What has happened is that a drug that was excellent for secondary prevention-that is, in people who suffer from heart disease-has been moved to primary prevention," and is much less effective in that role.
The study examined the results of 13 randomized trials and concluded that the drugs, which have been the first-line treatment for hypertension for at least 25 years, produce a higher risk for stroke when compared with other drugs used for the same purpose. Dr. Lindholm emphasized that the results pertained only to people who had high blood pressure without heart problems.
(10/20/05)- A large federally sponsored study found that the usage of statin drugs is even greater than originally believed. The study, the National Cholesterol Education Program involved more than13,000 adults. It found that use of statin drugs nearly tripled to 9.3% of adults age 20 and over, compared with a similar-size survey taken between 1998 and 1994.
Among men 60 and over, statin use nearly quadrupled to 24.3% from 6.8%, while it jumped to 21.6%, from 8.7% in women that age. The study's lead researcher was Margaret D. Carroll, a researcher at the CDC.
On June 23, 2006 Merck is slated to lose its patent for its statin drug Zocor (simvastatin). The company may try to extend the life of the patent, but some of the prescription benefit managers (PBMs) will be taking steps to get their members to switch to generic versions of the drug as soon as they can.
Express Scripts, said it would drop Lipitor (atorvastatin) from its list of preferred drugs. At the same time it will lower the co-payment cost for those taking the generic version of Zocor. WellPoint Health, the nation's largest health insurer will offer its members a four to six month free supply of the generic version of Zocor. Ivac, a generic drug manufacturer will produce a generic version of Zocor as soon as it can do so legally.
Merck has introduced another anticholesterol drug, Vytorin, which combines Zocor, which decreases the bad LDL, with Zetia, a medicine from Schering-Plough, that is not a statin, but acts to increase the level of the good cholesterol, the HDL.
(9/5/05)- Researchers who studied the records of more than 170,000 heart-attack patients concluded that the risk of death was reduced by about 50% if a statin drug is administered to the patient right away. Gregg Fonarow, a cardiologist at the University of California led the study group that was funded by Genentech Inc., which currently does not make a statin drug. Dr. Fonarow has done research for several companies that make statins.
The results of the study were published in the September issue of the American Journal of Cardiology. Those given statin drugs before hospitalization and within 24 hours after a heart attack had a 54% lower risk of dying in the hospital, compared with those not given the statin drug. According to Dr. Fonarow: "We also found that statins provided additional protection from other heart-attack complications."
(7/12/05)- The National Institute of Health's Heart, Lung and Blood Institute will provide about $22 million in funding for a six-year clinical study to see if raising "good cholesterol" (HDL) with a drug based on the vitamin niacin, while lowering "bad cholesterol" (LDL) with a statin, can prevent more heart disease than the statin alone. Pfizer Inc. is spending more than $600 million on clinical tests of a combination of its drug Lipitor and torcetrapib, an experimental drug that raises HDL levels.
The study is expected to involve 3,300 patients,l about a third of them being women. Prospective candidates for the study must have existing cardiovascular disease and be candidates for drug therapy. The patients will receive either simvastatin, the generic name for Merck's cholesterol lowering drug Zocor (simvastatin) plus Niaspan, an extended-release form of niacin available by prescription from Kos Pharmaceutical Inc. of Cranbury, N.J. Zocor will lose its patent in 2006, so Kos will apply to the FDA to sell the combined pill thereafter.
Kos presently sells Advicor, a combination of Niaspan and lovastatin, a generic form of Merck's statin drug Mevacor, whose patent has already expired. Kos will also contribute about $20 million in unrestricted financing towards the study. The study is expected to begin in about 50 to 60 clinical sites in the U.S. and Canada in November.
(7/6/05)- According to a new analysis of the large "Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial" (Allhat) which was conducted in 2002, diuretics worked equally as well as or better than newer more expensive drugs. Included in this latter category of drugs are ACE inhibitors and calcium-channel blockers in protecting against heart attacks and offer more protection against congestive heart failure.
The results of the new study were published recently in the latest edition of the Archives of Internal Medicine. The study group was led by Jeffrey Cutler, a senior adviser at the National Hear, Lung and Blood Institute a unit of the National Institute of Health
(7/2/05)-The FDA accepted the recommendation of its advisory panel and approved for immediate sale NitroMed (Lexington, Mass.)drug BiDil for heart failure to Afro-Americans. The drug makes it easier for the heart to pump by relaxing blood vessels. The drug had been rejected in 1997 by the FDA for use in all patients after two clinical trials conducted in veterans hospitals did not show statistical benefit.
It is the first time a drug has been approved by the FDA for one particular race. No one is sure why BiDil works better in blacks than in others. Some scientists theorize it works because it increases the body's level of nitric oxide, and this deficiency is more common in blacks than other races. An estimated 5 million Americans, 750,000 of them black suffer from heart failure.
Schwartz Pharma Manufacturing of Seymour, Ind, is manufacturing the tablets. The tablet is a combination of two generic drugs that are already on the market. These two drugs are hydralazine and isosorbide. NitroMed has not announced yet what price it will charge for the medication.
BiDil was the discovery of Dr. Jay N. Cohn, a cardiologist at the University of Minnesota, who in the 1970's began experimenting with vasodilators, or vessel-widening treatments for desperately ill patients. The FDA denied BiDil's approval in 1997, after determining that Dr. Cohn's results were not statistically significant.
The drug is to be taken three times a day, in addition to the heart failure medication that a patient is already taking.
(6/7/05)- The journal, Circulation, which is published by the American Heart Association had the results of a study that was done under the leadership of Dr. Richard H. Karas of Tufts University that concluded that AstraZeneca's Crestor had higher rates of some serious adverse effects than did some of the other statin drugs.
For the four drugs studied, the absolute rate of adverse events per million prescriptions was low: 28 for Crestor, 13 for Zocor, 3.5 for Pravachol and 4.3 for Lipitor. The authors of the study did not call for the removal of Crestor from the market. The FDA said that it stood by the results of its study announced in March, when it rejected a petition filed a year earlier by Public Citizen which claim the risk from usage of Crestor was too high for muscle and kidney damage.
The FDA concluded that "all the available evidence" showed that Crestor had no greater risk of muscle toxicity or serious kidney damage that the rival statins, Lipitor, Pravachol and Zocor. Each patient should be evaluated individually by his or her own physician to determine which of the statins would be the best choice for that particular patient.
(4/26/05)-Two studies, involving a total of 50,000 participants in which heart-attack patients were given Plavix as well as a clot-busting drug and aspirin as emergency treatment indicate an enhance chance for survival and even prevent the onslaught of a second heart attack.
In the bigger of the two studies, there were 7% fewer deaths in patients given Plavix. In the smaller of the studies there were 20% fewer serious heart "events" after 30 days, including death and a second heart attack. The combined treatment also helped to keep affected arteries open, which improved long-term recovery and survival from a heart attack.
Plavix, known generically as clopidogrel, is co-marketed by Sanofi-Aventis SA of Paris and Bristol-Myers Squibb Co., both of whom were sponsors of both of the studies. Marc Sabatine, a cardiologist at Brigham and Women's Hospital, Boston was the lead researcher in one of the studies where a 300-mg dosage of Plavix was administered, while the other one was a collaboration between researchers at Oxford University in London, and researchers in China where a 75-mg daily dosage of Plavix was administered.
A major new study suggests that all chronic heart patients would benefit from lowering their bad cholesterol level (LDL) to levels below 80. Last summer, the American Heart Association issued updated cholesterol-treatment guidelines suggesting that doctors consider getting the LDL in very high-risk patients to below 70, based on another study showing significant benefits for high-dose versus moderate-dose treatment with statins.
The study involved 10,001, and it was led by John LaRosa, president of State University of New York Downtown Medical Center, Brooklyn. Pfizer sponsored the study that involved the administration of its 80-mg Lipitor compared to its 10-mg version of the same drug. The result of a comparison study of Prizer's Lipitor and Merck's Zocor is expected shortly.
The average adult in the U.S. has an LDL of about 127, according to the American Heart Association. The new study showed a small increased risk of liver inflammation at the higher dose. In the study, 60mg patients reached an average LDL of 77, compared with 101 for those on the 10-mg version of Lipitor At the start of the study the average patient had an LDL reading of 98. After 4.9 years, 10.9% of the patients in the 10-mgs group and 8.7% of patients at 80-mgs had suffered a major event such as a heart attack, stroke or death from heart disease.
(3/5/05)- The American Heart Association has endorsed heart scans as another tool in evaluating a person's risk of having a heart attack. It can be used along with other medical evidence in determining how aggressively a person should be treated to prevent a heart attack. The test typically costs between $250 to $400 and is available in two different types of technologies: electronic beam technology (EBT) or fast computerized tomography scans.
The EBT is the preferred approach because it is more accurate and exposes patients to significantly less radiation than the computed tomograpghy, or CT scans. The tests show the calcium deposits in the patients' arteries. A high measure of calcium increases a patient's risk of having a heart attack.
Steven Nissen, a cardiologist at the Cleveland Clinic stated that the test for C-reactive protein is a more accurate predictor of a patient's heat attack risk. That test which costs as little as $8, which when added to other data provides plenty of information about the patient in evaluating the risk according to Dr. Nissen.
(1/15/05)-A FDA advisory panel voted 20-3 against allowing Merck's application for its cholesterol-lowering drug Mevacor to be sold without a prescription as an over-the-counter medication. A spokesman for Merck and Johnson & Johnson, who had joined Merck in the application, said that they would continue to try and gain approval to sell the drug as an over-the-counter medication. The FDA typically adheres to the recommendations of its advisory panels.
An advisory panel had previously denied similar applications in 2000 to sell statin drugs over-the-counter from Merck for Mevacor and Bristol-Myers for Pravachol. It is estimated that there are over 39 million Americans who are in the moderate risk category because of their cholesterol levels, who might benefit from taking statin medications.
The panel concluded that medical management is required for patients taking statin medications. The patent for Mevacor has already expired, but Merck's statin medication Zocor first goes off patent next year. If a brand name drug company produces a patented drug as an over-the-counter medication, it can gain at least 6 months of exclusivity for its product. Pfizer's Lipitor is the number one selling statin drug with over $9 billion in sales in 2004. Merck's Zocor is the number 2 seller in this market and Bristol's Pravachol is number 3.
One of the voting members of the panel, Dr. Bolsey Barnes, a Washington physician said, "A healthy lifestyle, low-fat diet and exercise may achieve the same result of O.T.C. statins,".
(1/14/05)- A study involving women ages 50 to 79 conducted over a long period of time concluded that the women who took calcium channel blockers in combination with diuretics had a higher death rate than women who were on a combination of beta blockers or ACE inhibitors and diuretics. The researchers in the study followed the women for an average of nearly 6 years. The U.S. government sponsored the study.
Calcium channel blockers relax blood vessels and reduce the heart's workload by affecting the movement of calcium into cells. Diuretics rid the body of excess sodium and water. Sylvia Wassertheil-Smoller, a researcher at Albert Einstein College of Medicine was the study's lead author. The number of heart related deaths was small: 31 out of 1,223 women taking the calcium channel blocker combination had fatal heart attacks versus 18 out of 1,380 on the beta blocker combination and 17 out of 1,413 on the ACE inhibitor combination had fatal heart attacks.
The women involved in the study had hypertension but no history of cardiovascular disease.
(11/18/04 )-A clinical trial involving about 10,000 patients with acute coronary syndrome will compare the effects of Vytorin and Zocor. Vytorin is a cholesterol lowering medication from a joint venture between Merck and Schering-Plough. Zocor is a cholesterol-lowering statin drug from Merck. In the case of Vytorin, it is hoped that a combined pill from Merck and Schering will both lower the level of bad cholesterol (Zocor from Merck) and increase the level of good cholesterol (Zetia from Schering).
The FDA approved the statin drug Vytorin in July for the treatment of high LDL. The purpose of the trial is to assess whether Vytorin is more effective in reducing mortality and morbidity in heart patients versus Zocor alone by dramatically lowering harmful cholesterol levels though dual inhibition.
The results of a study of increased dosage of Zocor indicated that increased dosage of the drug to 80 mgs did not benefit patients who had previously had heart attacks. In fact in did slightly increase the risk of muscle-related complications. Zocor is the second best selling of the 6 statin drugs now on the market. Lipitor is the biggest seller in this group.
Merck, the manufacturer of the drug, paid for the experiment, which included 4,497 patients. Dr James A de Lemons, a cardiologist at the University of Texas Southwestern Medical Center was the principal author for the study. One group of 2,265 patients was given 40-mgs dosages of Zocor for 30 days and then the dosage was increased to 80-mgs. A second group of 2,232 patients took placebos for four months and then was given 20-mgs doses of Zocor for the balance of the experiment. The two groups were followed for up to a period of 2 years.
In a similar experiment involving Lipitor the increased dosage of that drug to 80-mgs did not result in muscle-related complications. The 40-mg dosage of Zocor did not result in any increase risk of muscle-related complications.
The FDA has granted approval to Pfizer Inc. to advertise and include on the label for Lipitor that it cuts the risk of heart attacks, angina and the need for surgery or angioplasty to open clogged arteries feeding the heart. Up until now the drug could only be marketed for its ability to lower cholesterol levels. Zocor from Merck & Co., and Pravochol from Bristol-Myers Squibb Co. have been allowed to include on the label and in ads that they have the power to cut heart attacks for almost 10 years already.
The changes stem from the results of a company-funded study called the Anglo-Scandinavian Cardiac Outcomes Trial or Ascot, which involved more than 19,000 patients with high blood pressure. It showed that Lipitor reduced the risk of heart attacks and heart-related deaths by 36% compared to the placebo.
Not all experts are jumping on the bandwagon in favor of the new lower levels of cholesterol as recommended by the National Institutes of Health, in conjunction with the American Heart Association and the American College of Cardiology. Some experts say statins are more complex than their status suggests, and like all other drugs they may have some serious negative side effects. It has yet to be proven that the drugs will not have a serious toxicity effect when taken over a 20 year or longer period of time.
Some consumer groups have said the new recommendations are tainted by the influence of drug companies that make statins and finance research on the drugs. One of the consumer groups, the Center for Science in the Public Interest in Washington asserted that many of the experts on the panel that drew up the guidelines had received consulting fees, money for research or other money from the companies that make the statins. The NIH has acknowledged that eight of the nine experts on the panel that issued the recommendations had received financing from one or more or the companies that make statins.
The FDA has granted approval to Schering-Plough Corporation and Merck & Co. to begin marketing Vytorin that will thus become another competitor in the cholesterol drug market. The drug combines the properties of Zocor from Merck and Zetia from Schering to both lower the bad cholesterol number (LDL) while at the same time increasing the good cholesterol number (HDL).
Merck said that it would begin an aggressive marketing campaign to get people to switch to the new drug since its patent for Zocor expires in 2005. Global sales of cholesterol drugs are expected to exceed $21 billion in 2004, with Pfizer's Lipitor being the leader in sales with expected sales of over $9 billion in 2004.
In a study, researchers from Brigham and Women's Hospital in Boston and Harvard Medical School concluded that genes may play an important part in determining who benefits from taking statin medication in the battle against heart disease and failure. All of the 1,500 patients in the study were taking Bristol-MyerSquibb Co. cholesterol statin drug Pravachol.
Ten different genes were used in the study. Patients with a certain common genetic variant had a 22% smaller drop in total cholesterol and a 19% smaller drop in LDL or "bad" cholesterol than those patients with the variant. Bristol-Myers called for further study of all statin drugs in connection with these findings. The relevant genetic variant was found in 7% of the patients studied. Paul M. Ridker who is a director of the Women's Hospital's Center for Cardiovascular Disease Prevention was the lead author of the study.
The investigators will now study the Pfizer's statin medication Lipitor to see if the same results will apply to this medication. Lipitor is the biggest selling drug in the world, with an expected close to $10 billion in sales expected in 2004. There are plans to compare the results of different dosages of the statins to see if there is any correlation to this genetic evaluation.
Proponents of personalized medicine, which is called pharmacogenics feel that this is one of the most important factors that should be used by a physician when he is prescribing medication to his/her patients. SmithKline PLC, has a genetic-research team headed by a former Duke University researcher considered a pioneer in this field. Bristol-Myers is also doing in house research in this field.
Dutch medical regulators, acting on behalf of the 24 members of the European Union issued a warning in connection with some serious side effects involved in the usage of AstraZeneca's statin drug Crestor. Following this warning the FDA issued an advisory warning doctors in the country to carefully read the U.S. label, which has cautions similar to the new European label.
Concern over the usage of Crestor has arisen because of reports of serious muscle toxicity in some patients since its introduction last year. The new label warns doctors to start all patients on a low dose of 10-mgs, and to restrict high doses of 40-mgs to special cases. Public Citizens, a consumer group, petitioned the FDA in March 2003 to remove Crestor from the market, citing seven reported cases of rhabdomyolysis in the U.S., Canada and the United Kingdom.
Rhabdomyolysis is a rare muscle-wasting condition that caused Bayer AG to withdraw its statin drug Baycol after more than 30 patients in the U.S. reportedly got the disease and died while taking the drug. An analysis published in the New England Journal of Medicine in 2002, based on FDA and industry data, found that the reported deaths appeared far more frequently for Baycol than for any other statin.
According to industry figures the sales of Crestor were about $129 million in the first quarter of 2004. Pfizer's Lipitor, the leader of the statin drugs sold about $2.5 billion in the same quarter, while Merck's Zocor garnered about $1.3 billion and Novartis' Lescol had about $173 million in revenues for the quarter.
England became the first country in the world to approve a statin for sale as a generic drug. Experts in England recommended last year that pharmacists should be able to supply their customers with the generic version of Merck's Zocor following some simple recommended checks that would be done in the pharmacy. An advisory panel to the U.S. FDA may consider data in support of allowing nonprescription sales of statins within the next year.
Merck's Zocor lost patent protection in Britain in 2003, and the company is anxious to be the leader for sales of the non-prescription version of the drug so that it can make up for lost sales. McNeil Europe, a division of Johnson & Johnson is expected to launch its generic version of Zocor at the end of June or early July. It will be in doses of 10-mg per 28-day pack and will be called Zocor Heart Pro. Generically the drug is called simivastatin.
Merck and J&J have formed a joint venture in the U.S. to sell Merck's statin drug Mevacor without a prescription sometime next year. Pfizer's Lipitor is the leading prescription drug sold in the world with sales last year exceeding $9.23 billion.
A recent study of the performance shows that there is a positive in the treatment of Type 2 diabetes as a result of the patient taking one of the stain, namely a 40-mg dose of simvistatin. Researchers are now studying the effect on Type 2 diabetes with an even stronger dosage of simvistatin. About 16 million Americans have Type 2 diabetes, and there are about 800,000 new cases detected each year.
As a result of the study new guidelines have been published by the American College of Physicians that call for people with diabetes who are older than 55, and for younger patients who have any other risk factors for heart disease, like high blood-pressure or a history of smoking. According to Dr. Sandeep Vijan of the University of Michigan: "almost everyone with Type 2 diabetes should be on a statin."
The guidelines are based on a review of studies that show that statins reduce the rate of heart attacks and other heart-related illnesses by 22% to 24% among people with diabetes who had average or above average risks of cardiac disease. Dr. Vijan emphasized that controlling hypertension remained the highest priority. Ranking second is the control of lipids, the fat in the blood stream that can affect coronary health, ahead of glucose regulation
Although the HDL level averages about 45 for American men and 55 for American women, is there any proof that having a higher level will actually prevent a heart attack or stroke? On the other hand as many as half of all heart-attack victims have LDL levels that are considered normal. There are three components of a person's total cholesterol level, i.e. LDL, HDL and triglycerides. HDL is the only one of the three where higher is considered better.
In a very small study involving just 19 patients researchers found that an experimental drug from Pfizer Inc. named torcetrapib both increased the HDL and lowered the LDL of the patients. The patients in the study took a 120-milligram torcetrapib pill daily for four weeks; 10 also took the Pfizer's cholesterol lowering pill Lipitor every day. The HDL levels rose an average of 46% in those taking just torcetrapib, and increased 61% in those getting both medications. Six patients took the torcetrapib twice a day in the study's third phase, and their HDL jumped 106%. LDL levels, the bad cholesterol, fell an additional 17% beyond the reduction achieved by Lipitor alone. Side effects in the study were mild.
Dr. Daniel Rader, director of preventive cardiovascular medicine at the University of Pennsylvania, is the study's senior author. He stated: "One of the big questions that we do have with this drug is will using it to raise HDL levels from normal to high actually reduce risk in people who are at high risk?" Research was also conducted at Tufts University. Pfizer, a branch of the National Institutes of Health, the University of Pennsylvania and the New England Medical Center, funded the study.
HDL takes away bad cholesterol, the main ingredient in artery plaques that rupture to cause heart attacks. This study and its results are only the first step in a long process before any definite final results are obtained. But Pfizer has stated that it intends to eventually market the torcetrapib pills, if successful, only in combination in one pill with Lipitor. Patients who use any other cholesterol-lowering drug will not have access to torcetrapib. The combination Lipitor-torcetrapib pilll would have a one-two punch in that it both lowers the LDL levels and increases the HDL level at the same time. At the same time the new pill would protect Pfizer's patent protection for Lipitor, its $9 billion best selling drug in the world.
Pfizer indicated that it intended to actively pursue the issue of HDLs when it acquired Esperian Therapeutics, a tiny biotech startup company for $1.3 billion because if its novel work in connection with HDL products. These include an intravenous drug that might be used to melt plaques in patients having heart attacks. Pfizer will test the combination 60- mg torcetrapib with different doses of Lipitor to see which might be the most effective combination of the two pills. Ultrasound images will reveal whether dangerous plaques have regressed as a result of the treatment. The initial test will be done over a two year period with about 13,000 patients being studied.
The National Institute of Health has announced that it intends to use about 600 medical professionals to spread the word to doctors that diuretics should be the first medication used in the battle against hypertension. These medical professionals, including doctors, will be used in a similar manner to how the drug industry uses "detail " salesmen and saleswomen to help promote their drugs. Some states have adopted this plan in fighting the high cost of Medicaid drugs being prescribed by some doctors when other generic or cheaper brand name drugs can accomplish the same results.
The NIH's plan is going to be carried out over a three-year period of time and also will involve new hypertension guidelines. The study involved some 33,000 patients and is known as the "Allhat" study whose results were published in 2002. The study was led by Paul Whelton, senior vice-president of health-science at Tulane University The study cast doubt about the effectiveness of the statin medications in benefiting or even significantly reducing the chance of a major heart problem. Bristol-Myers statin medication Pravochol was the one used in connection with the "Allhat"study.
The study known as the Allhat study indicated that patients on diuretics had better blood pressure control, fewer strokes and less congestive heart failure than did the other patients who were not on diuretics. The study further determined that those patients who were on calcium channel-blockers had little, to no benefit in lessening the number of heart attacks, or were helped in the prevention of heart-related deaths.
The study has lasted for 10 years, and determined that diuretics are the best first option for people suffering from high-blood pressure. There has been a loud uproar from the medical profession in regards to this opinion. A diuretic costs as little as $36-$96 annually, while a calcium channel blocker such as Novarsc costs about $724 a year, and Accupril, an ACE inhibitor costs about $470 a year. Beta-blockers, which are earlier medications than the ACE inhibitors cost between $240-$667 per year.
An Australian study has given the opposition some factual material to base their dissent on. The Australian study observed 6,083 hypertensive patients over the age of 65 for a median period of 4.1 years. The patients were started on either a diureticof an ACE inhibitor. The Australian government and Merck & Co funded the study. Many physicians feel that a combination of diuretics and ACE inhibitor, Beta-blocker or calcium channel-blocker is the most appropriate was to treat patients suffering from heart problems. Each patient must be treated on an individual basis since there is no hard and fast rule in these situations.
As a follow up to our item about the C-reactive protein (CRP) blood test in this article several weeks ago, the Centers for Disease Control and the American Heart Association have issued guidelines for the usage of this test. The test is not a replacement for traditional cholesterol and blood pressure tests. It should be used for patients whose risk already appears to be high from these other tests.
Are the statins, the cholesterol-lowering class of drugs safe enough to be used without a doctor's prescription? In the year 2000 the FDA considered this question, and the answer that they came up with was a negative one. A joint venture between Merck & Co., and Johnson & Johnson will raise this question again when they seek permission to be able to sell Merck's Mevacor, which is the oldest statin drug, over-the-counter.
Lurking in the background is Bristol-Myers Squibb, which may also seek permission from the FDA to sell its cholesterol lowering statin drug Pravachol as an over-the-counter medication. Please keep in mind that the statin class of drugs had about $12.5 billion in sales last year in the U.S., making them the best selling class of drug in the U.S.
In the accompanying chart we list some of the risk factors, and the levels to consider for being at risk for a heart attack:
HDL (good cholesterol)
Body Mass Index
Key Levels to Watch
3mg/L or higher
200 mg/dL or higher
40/dL or lower
115/75 or higher
25 or higher
Cardiovascular disease was responsible for the death of about 950,000 people in the U.S. last year. This means that one in every 2.5 deaths had some connection to cardiovascular disease. It is estimated that there are about 8 million Americans taking one of the statin drugs. Pfizer's Lipitor is the number one seller, garnering an expected over $6 million in sales for the drug this year.
Although it may seem strange that the drug companies are seeking to sell the product before the expiration of the patents on these drugs, there is a very valid reason in back of their behavior. Recent studies and medical guidelines have shown that more people could benefit from taking the anti-cholesterol drugs. If the drug is sold as an over-the-counter medication, it probably could increase the number of people taking the drug at least twofold. Thus although the price that the medication is sold at would come down sharply, the increase in sales would more than make up for the drop in price.
One of the key questions that needs to be answered when using a statin is how harmful it will be to the liver. Many present users of these drugs have had some negative side reactions when they have taken the drugs. Muscle spasms and bowel irregularity are but two of these negative reactions that are the most common for those who are on the medication.
On the other hand Pfizer might continue to argue for Lipitor as a prescription only medication, advertising that it is "better" than the over-the-counter. Keep in mind that the statins lower the "bad"cholesterol (LDL-low density lipoprotein) when in fact several of the latest studies indicate that elevating the "good" cholesterol (HDL- high density lipoprotein) is much more important in trying to prevent cardiovascular events. Another factor that has come into the equation lately is the level of C-reactive protein.
Most medical professionals feel that a "good" HDL reading should be at least above 40 mg/dl in men and 50 in women. A "bad" LDL reading should be 110 or lower. The greatest benefit would come if the HDL level exceeded 60. Although there has not been too much controversy over the higher the HDL level the better, there is a great deal of controversy over whether or not there is any benefit from having a LDL of less than 110. Many health professionals feel that the HDL level is so important that it can literally wipe out other risk factors, like smoking and being overweight.
Total cholesterol, which is based on a combination of LDL, HDL and triglycerides, should be less than 200 mg/dl. Research has shown that for every one-unit increase in HDL, a person's risk of heart disease drops b as much as 3%. No one is exactly sure why the HDL appears to offer so much protection against heart attacks. Losing weight and quitting smoking are two obvious ways to lift the HDL level. High fat foods lift the HDL but they are associated with heart disease. Cutting down on calories and switching the fats in your diet to monounsaturated fats are better for your heart, and help stabilize your HDL level.
Depending on the type of exercise that you do, can benefit your HDL level also. Weight lifting does not help raise your HDL level but aerobic exercise does. The biggest exercise-induced boost in HDL was found to come from intensive training, such as training for marathons. Moderate alcohol consumption can increase your HDL level also. Niacin a B vitamin can raise HDL by 15% to 30%. Drugs known as fibrates (gemfibrozil) can raise HDL levels by 10% to 20%. Unfortunately once you stop taking a HDL booster drug, it reverts back to its previous level.
In a study funded by Pfizer, that was done at the Cleveland Clinic, researchers found that the people getting Pfizer's Lipitor (atorvastatin) had much lower LDL levels than did those patients who were taking Bristol's Pravachol (pravastatin). Dr. Steven Nissen, who heads the Clinic and is the medical director also asserted that the Lipitor patients also had a slight reduction (-0.4%) in the volume of plaque, while the Pravachol patients had a slight increase (+2.7%) over an 18-month period. Thus in effect the pravastatin did not stop the coronary artery disease, while the atorvastatin did stop it.
Medical experts said that national guidelines were unlikely to be changed until additional studies found that more aggressive cholesterol lowering resulted in a reduced risk of heart attacks and/or deaths. Please keep in mind that AstraZeneca's new statin lowering drug Crestor (rosuvastatin) can lower LDL levels more than Lipitor. According to Merck, its cholesterol lowering medication Zetia (ezetimibe) taken in combination with another type of drug will lower the LDL levels even more than any other statin.
The study also showed that those patients on Lipitor had a drop of 36% in their C-reactive protein levels in the 18-month timeframe while those on Pravachol only had a drop of 5%. In the study, patients were assigned to either 80-mgs a day of Lipitor, or 40-mgs a day of Pravachol. These were the strongest doasges of these drugs at the time the study commenced, but there is now an 80-mg a day version of Pravachol also.
Please see our earlier article on this topic: Beta Blockers, ACE Inhibitors and Statins in the Battle Against Heart Disease or Failure-Part I
We first began to look at heart failure in our article "Cardiovascular Disease: Congestive Heart Failure". Since that original article we have followed up with several other articles on the topic of prescription drugs. In our article "Prescription Drugs and the Cost of Advertising Them" we discussed how on average the cost of advertising prescription drugs is rising at a much higher percentage than is the cost for Research and Development. Please also see our articles " Prescription Drugs and the Elderly" and "Prescription Drugs and Medicare".
FOR AN INFORMATIVE AND PERSONAL ARTICLE ON PRACTICAL SUGGESTIONS WHEN SELECTING A NURSING HOME SEE OUR ARTICLE "How to Select a Nursing Home"
By Allan Rubin
updated April 26, 2017