Thursday, June 20, 2013

Coffee, Chocolate and Your Heart

     There have been three studies released recently, dealing with the effects of coffee, coffee and tea, and chocolate on the heart. The studies variously showed a small reduction in both systolic and diastolic blood pressure or a reduced risk of heart failure. Once again, these studies are suggestive, but larger and more complete studies are necessary to reach a firm conclusion. And let us not lose sight of the fact that none of the studies showed the consumption of coffee or tea or chocolate to have a deleterious effect on heart function or blood pressure. The benefit of chocolate is presumed to be the result of flavanol in the chocolate; this compound increases the formation of nitrous oxide and thereby dilates the arteries ( much as Viagra does).

     One study was done by Dr. Karen Ried of the University of Melbourne, Australia. This was a review of 20 short term studies involving over 900 volunteers. The studies lasted 2 weeks, 8 weeksa, or 18 weeks.They ate 100 gm of chocolate daily, and averaged a 3mm drop in systolic pressure and a 2mm drop in diastolic. One study showed a drop of 4mm and 3 mm, respectively. This is the same effect you would see from daily exercise or a heart-healthy diet. The control group showed no such decrease. The article also mentioned the Kuma Indians of South America who average 4 cups of cocoa a day and have remarkably good blood pressure.

     Another study was a meta-analysis of 5 studies. There was a j-shaped curve relating the consumption of coffee to heart failure. The biggest "protection" against heart failure came with those who averaged 3 to 5 cups of coffee a day. The results of this study might make one reconsider the recommendations against coffee consumption in certain patients.

     The final study was a French retrospective analysis of over 175,000 patients ranging in age from 16 to 95 years with regard to their consumption of tea or coffee. They subdivided the patients into 3 groups: no coffee or tea, one to four cups a day, and more than four cups daily. In those drinking 1-4 cups a day, there was a small decrease in systolic blood pressure, in pulse pressure, and in pulse rate. The effect was small, but it is suggestive.

     To me the take away message from these studies is that there is no evidence that the consumption of tea, coffee or chocolate is detrimental, and it may in fact be beneficial.


Wednesday, June 19, 2013

NSAID pain pills and heart disease

     Recently there was an electronic pre-publication ahead of print by Lancet, the British medical magazine. The article (and the accompanying editorial) discussed the result of a meta-analysis (and see my prior blogs for the errors inherent in meta-analyses) of 639 randomized trials of Cox-inhibitors (such as Celebrex) and NSAIDs (ibuprofen or Motrin/Advil, naproxen or Aleve, and diclofenac or Voltaren) to see if their use (a) caused increased upper GI bleeding and/or (b) increased vascular events (heart attack, heart failure, stroke). You may recall that Vioxx, a cox-inhibitor, was taken off the market because of an increased incidence of cardiac events.

     The results were first announced as an increase in relative risk, which always looks worse than the increase in absolute risk. The studies looked at the effect of either a standard dose of a coxib, or a high dose (150mg diclofenac, 2400mg ibuprofen, 1000mg naproxen). The studies looked at major vascular events (heart attack or stroke), heart failure, overall mortality, and upper GI complications.

     There was an increase in major vascular events of 33% with the use of  Celebrex and Voltaren. There was also an increased risk with Motrin, but it did not reach clinical significance. There was no increased risk with Aleve. OTOH, the use of Aleve was associated with the greatest risk of upper GI bleeding compared with the other three drugs. And only coxibs showed a statistically significant rise in all-cause mortality.
In the case of vascular events and upper GI bleeding, the greatest risk factors were age, and conditions (diabetes, hypertension, GERD) that pre-dispose to a problem.

     Now for the absolute numbers, which illustrate the real risk. Using a coxib or diclofenac was associated with 3 additional vascular events per 1,000 person years, one of which was fatal. If a patient had a 2% annual risk of a vascular event, then a coxib would add 7 additional events per 1000 patient years (2 of which would be fatal), Voltaren would add 8 (2 fatal), and Advil would add 9 (3 fatal).

     In patients with a 0.5% annual risk of upper GI complications, coxibs and diclofenac would add 4 more events per 1000 patient years, ibuprofen 15 more events, and naproxen 16 more.

     All four drugs showed a statistically significant increase in hospitalizations due to heart failure.

     Once again, we see that the absolute risk seems less serious than the relative risk, as is almost always the case. Also, no studies were done at a lower dose of the drugs, and no studies were done to see if the addition of a PPI or other acid inhibitor lessened the risk of upper GI complications.

     The data thus shows a small but statistically significant risk with some of these drugs to cause problems.
These problems occurred more frequently in high risk groups, and you should discuss with your doctor which group you fall into. To my mind, the data is barely significant, and the use of these drugs is a judgment call, and one has to compare quality of life to statistical risk.

Sunday, June 9, 2013

Coenzyme Q-10

     After I mentioned the effect of statins on muscles and referred to coenzyme Q-10, I have received a number of questions about this ubiquitous molecule,  so I thought I would answer a few of them here.

     Coenzyme Q-10 is contained in animal foods that we eat, but over 90% of this molecule is synthesized in the body. Curiously enough, it shares a common molecule with the synthetic process for cholesterol. The subscript "10" refers to the number of side chains. This is important, because lab rats synthesize and use Co-Q-9, which is chemically different, so the results with lab rats should not be extrapolated to human use. Your tissue level of CoQ decreases with age, chronic heart failure, diabetes, some cancers, and HIV, but adding CoQ to the diet has not been shown to benefit any of these conditions. It will, however, help protect the heart from the side effects of doxorubicin, an anti-cancer drug, and does help the immune system of lab rats.

     As I mentioned in my earlier blog, CoQ is a vital molecule for the electron transport chain that lets the cell generate aerobic (requiring oxygen) energy, which accounts for over 90% of the body's requirement. No other molecule in the body can do this job.The molecule was discovered in 1957, and is found in the membranes of many cell organelles, especially in mitochondria, the energy factories of the body. The molecule is fat-soluble,  and also has anti-oxidant properties as well as the ability to regenerate other antioxidants such as Vitamin E.

     Because the molecule is fat soluble, absorption is best when taken with food. A typical dose is 150 to 300 mg/day. It was found that it may help some migraneurs, and when taken with magnesium citrate and Vitamin B2 (riboflavin) help prevent migraine attacks in some patients. Because it shares a common molecule with the synthesis of cholesterol, statins, which reduce the level of cholesterol, also reduce the level of CoQ. Oddly enough, some beta-blockers also reduce the tissue level of CoQ.

     There are few studies that show any unequivocal benefit from taking CoQ-10. It does improve the immune system of lab rats, but not of humans. It also seems to protect lab rats from the damages of external radiation.The two interventional studies, one on patients with heart failure  and one on patients with breast cancer failed to show a significant benefit. Studies to see if CoQ supplementation increased the lifetime of lab rats led to contradictory results.
However, a meta-analysis (and see my previous blog for my critique of such studies) did show that Co-Q-10 lowered the blood pressure in humans, by as much as 15mm systolic and 10 mm diastolic, which is a very powerful result. No study has shown that Co-Q supplementation reverses the decrease of CoQ caused by statins.

     In summary, coenzyme Q-10 is a vital molecule for energy generation, and we are busily looking for a clinical use for supplemental doses.  I am looking forward to a double-blind study to validate its benefit in patients with hypertension, as well as  to see if it can prevent the muscle aches  and muscle breakdown that can develop with the use of statins.



Wednesday, June 5, 2013

Pancreatic Cancer, Pancreatitis, and Diabetes.

     There was an article last week (Friday, May 31) on the front page of the business section of the NY Times quoting an interview with a doctor who claims that he has evidence that a diabetes drug, Januvia, can predispose the users to pancreatic cancer, based on animal studies.

     First, let me say a few words about all drug/animal studies. Animals have very different biochemical milieus than do humans, and the results of animal studies may not apply to humans. As an example of the difference, every animal but man and the guinea pig have the necessary enzymes to synthesize ascorbic acid, or Vitamin C. So already their chemistry is different. It is not automatic that a drug that has effect A on animals will have effect A on humans, and vice versa.

     Several decades ago, Congress passed a law with the Delaney clause, saying that any food additive that caused tumors in animals could not be added to food for humans. Shortly thereafter it was found that saccharine caused tumors in mouse bladders. Since saccharine was the only synthetic sweetener then available, Congress immediately passed a law exempting saccharine. So even the lawmakers don't believe the animal-human link.

     The changes that Dr. Peter Butler found were "pre-cancerous" lesions in rats, and no one knows how many precancerous lesions progress or what the time frame is. Post-marketing surveys have found no increased incidence of pancreatic cancers in users of Januvia, but there is argument as to whether or not there is an increased incidence of pancreatitis. As I have said before, if you have to argue about the significance of data, it almost certainly is not significant.

     What are the risk factors for pancreatic cancer? Age, obesity, chronic pancreatitis, and diabetes. The link with diabetes is tricky, because often pancreatic cancer first makes its presence known by causing diabetes. No one has shown that alcohol consumption is a risk factor for pancreatic cancer, even though it is a risk factor for chronic pancreatitis, and chronic pancreatitis is "linked" to pancreatic cancer, but not shown to cause it if you parse the observational data. OTOH extrapolating from diet studies, the Mediterranean diet should be protective.

     In summary, since diabetes itself is a risk factor for pancreatic cancer, the proper study would be to compare two groups of diabetics, one of whom takes Januvia while the other does not. And these patients should have the same diet vis-a-vis red meat and vegetables. I wonder if chronic pancreatitis is a risk factor for pancreatic cancer in lab rats? If it is not, then such a result would invalidate the  extrapolation from lab rats to humans.