June 22nd, 2012
Olmesartan Use Associated With GI Disorder That Mimics Celiac Disease
Larry Husten, PHD
A gastroenterologist at the Mayo Clinic has uncovered a rare but potentially serious association between the angiotensin II receptor antagonist (ARB) olmesartan and severe gastrointestinal problems that resemble Celiac disease. The report has been published online in Mayo Clinic Proceedings. In the U.S., olmesartan is sold as Benicar and, in combination with other drugs, as Azor, Benicar HCT, and Tribenzor.
Dr. Joseph Murray first suspected the connection when two patients with refractory Celiac disease experienced symptomatic improvement after discontinuing olmesartan treatment. He eventually identified a total of 22 people over 3 years with unexplained chronic diarrhea and enteropathy who were taking olmesartan. 14 patients had symptoms so severe that they were hospitalized. All the patients were unresponsive to a gluten-free diet and did not have tissue transglutaminase antibodies in the blood, which are used to detect celiac disease. After discontinuing olmesartan all the patients gained weight and had an improvement in symptoms.
“We thought these cases were celiac disease initially because their biopsies showed features very like celiac disease, such as inflammation,” said Dr, Murray, in a Mayo Clinic press release. “What made them different was they didn’t have the antibodies in their blood that are typical for celiac disease.”
[youtube=http://www.youtube.com/watch?v=KjIWzIUN-eA&w=600]
In a statement released on video, Murray emphasized that “the great majority of patients on this medication (olmesartan) do not need to do anything.” However, he recommended that patients taking olmesartan discuss this finding with their physician if they ”are experiencing GI symptoms or unexplained weight loss” or “if a diagnosis of celiac disease has been made in the recent past.”
Murray acknowledges that there is currently no evidence demonstrating a cause-and-effect relationship. “We’ve reported an association,” he said. “What needs to be known next is the science to understand why there is such an association.”
Hypertension expert Franz Messerli offered the following comment:
The report from the Mayo Clinic suggesting that olmesartan is associated with severe gastrointestinal adverse effects is of concern. Olmesartan sales have exceeded 500 million a year in the US alone and the drug, as are all ARBs, is perceived as being unique because of its paucity of side effects. Several issues should be scrutinized in this context:
1. Were any of the patients re-exposed to olmesartan and did the symptoms recur? Mere cessation of a drug and vanishing of a symptom is not an acceptable criterion for confirming a cause and effect relationship. Only systematic (and not anecdotal) re-exposure can confirm that the GI side effects were indeed due to olmesartan.
2. Has there been any other ARB indicted for the same issue or are the findings unique to olmesartan. Is this a class effect or is it specific to olmesartan?
3. Was this syndrome ever seen in the extensive data base with olmesartan or with any other ARB? There are numerous clinical trials with olmesartan and GI adverse effects are exceedingly uncommon.
4. And most importantly, what is the putative pathophysiologic mechanism? In this context the possibility of intestinal angioedema comes to mind which has been observed occasionally with ACE inhibitors but to my knowledge not with ARBs. If it were olmesartans’s inhibitory effects on transforming growth factor B action as the authors suggest, then this phenomenon should have been observed with other ARBs such as losartan and valsartan (which are more commonly prescribed than olmesartan) as well.
June 22nd, 2012
FDA Rejects ACS Indication for Rivaroxaban (Xarelto)
Larry Husten, PHD
The FDA has issued a complete response letter to the supplemental new drug application (NDA) for the proposed indication of rivaroxaban (Xarelto, Johnson & Johnson) in patients with acute coronary syndrome (ACS). The action was expected, since last month the FDA’s Cardiovascular and Renal Drugs Advisory Committee voted against recommending the new indication, which was based on the pivotal ATLAS ACS 2-TIMI 51 trial.
In a press release, a J&J company official said the company remains “confident in the robust results of the ATLAS ACS 2 TIMI 51 trial and the positive benefit-risk profile of rivaroxaban in patients with ACS. We will continue to work with the FDA to fully address their questions as quickly as possible.” Rivaroxaban is currently approved for the prevention of clots following knee replacement and hip replacement surgery and for the prevention of strokes and blood clots in people with atrial fibrillation.
June 21st, 2012
PTSD Relatively Common Among Patients with Heart Disease
Roughly 1 in 8 patients with acute coronary syndromes (ACS) subsequently suffers from post-traumatic stress disorder, according to a meta-analysis in PLoS ONE.
Researchers analyzed 24 studies comprising nearly 2400 patients with ACS. At a mean 5.7 months following an ACS event, 12% of the patients had clinically significant symptoms of PTSD assessed by questionnaires or clinical interviews. An analysis of three studies found that those with PTSD had double the risk for a subsequent cardiac event or mortality.
The authors caution that PTSD prevalence in the individual studies ranged from 0% to 32%, suggesting considerable heterogeneity. “Caveats aside,” they write, “there is now considerable evidence for a link between PTSD due to various life stressors and subsequent heart disease.” They propose that the effects of inflammation associated with PTSD may also affect the heart.
June 20th, 2012
C3 Global Summit, June 20, 2012
Aaron C. Earles, DO
The coronary track this morning began with discussions of the rationale for CTO interventions in “the era of appropriate use criteria” and of how to recognize unfavorable features for CTO PCI. The session concluded with two live case transmissions.
The first case was of a 55-year-old man, an exsmoker with a history of diabetes mellitus and hypertension, who presented with a proximal LAD CTO. The case was transmitted from Guangdong Provincial Hospital in Guangzhou, China. The patient had prior stenting of the LM and proximal Cx. He had been complaining of angina for 1 month. Stress imaging suggested anterior wall ischemia. The expert panel elected to attempt crossing the LAD from a retrograde fashion using a right-to-left collateral via the RCA. This case also used IVUS, which was a great review of yesterday’s topic.
The second case was transmitted from Lilavati Hospital in Mumbai, India. The patient was a 75-year-old without diabetes or hypertension who had a previous history of inferior-wall MI. He presented with complaints of exertional dyspnea. Echo showed LVEF of 55% with inferior septal and basal inferior-wall hypokinesis. Angiography revealed a 99% proximal calcific eccentric lesion, ostial LAD calcified lesion, followed by a mid-LAD bifurcation lesion. Because an IVUS catheter could not be passed through the RCA lesion, a rotational atherectomy device was used. After atherectomy, a 2.75-mm noncompliant balloon was used to post-dilate so that the IVUS catheter could pass. A 3.0-mm drug-eluting stent was selected for deployment in the lesion with post-dilation to 3.4 mm. Next the physicians used IVUS to evaluate the calcified lesions in the LAD. Rotational atherectomy was once again used to make the plaque more suitable for stent deployment in the bifurcation lesion. Unfortunately, the session ran out of time before the case was completed. Even so, the discussion was extremely helpful for us in attendance. So far, C3 has been a great learning experience for this Fellow. I will keep you posted!
June 20th, 2012
Reality Check: The ORIGIN of Spin in a Randomized Trial
Steven Coca, DO, MS
In the ORIGIN randomized trial, involving about 12,500 people who had diabetes or were at risk for it, insulin glargine showed no advantage over standard care in preventing the primary composite cardiovascular endpoints at a median follow-up of 6.2 years (see news coverage on CardioExchange). ORIGIN was a completely negative trial, yet in the article’s abstract the authors reported a benefit of basal insulin in the secondary endpoint of incident diabetes (odds ratio [OR], 0.80; 95% CI, 0.64–1.00; P=0.05) and stated that the treatment “reduced new-onset diabetes.” The discussion section of the paper further asserted that the treatment “slowed progression of dysglycemia.”
A few qualifications are in order:
1. This seemingly positive finding (in incident diabetes) was for only one of several secondary endpoints, and the alpha level needed to detect a difference was not corrected for multiple outcome assessments.
2. Among the 1456 participants without diabetes at randomization, only 44% of insulin glargine recipients and 47% of standard-care recipients underwent both prespecified oral glucose tolerance tests at the end of the study. So, in effect, fewer than half of the patients were assessed on the one, barely positive endpoint of incident diabetes. Plus, the fact that an absolute 3% more of the control group underwent the necessary testing could have resulted in ascertainment bias.
3. Incident diabetes among those 1456 participants was much greater than 10% (30% in the insulin glargine group, 35% in the standard-care group), but the authors reported an odds ratio rather than a relative risk, yielding an overinflation of the purported benefit: The relative risk would have been 0.86, compared with the reported OR of 0.80. (Only when the probability of a disease is low does the odds ratio approximate the relative risk.)
4. The upper boundary of the confidence interval included 1.00.
Despite these realities, Sanofi and the investigators didn’t hesitate to spin the trial findings to the media. The Sanofi press release stated, “…the results also showed that insulin glargine delayed progression from pre-diabetes to type 2 diabetes.” Sanofi’s VP of Medical Affairs said, “ORIGIN shows that it is possible to maintain low and stable HbA1c levels that are close to normal over a long time, and to potentially delay the progression from pre-diabetes to diabetes.” One of the lead investigators took this positive angle: “We know that in this study, insulin lowered blood sugar levels and did so safely and effectively. I can look at a patient and say, ‘Your blood sugar is not well controlled right now, so let’s go ahead and add insulin’.”
There is a temptation for those involved in a trial to present findings as positive, even if the positive aspect is only a morsel. However, scientists should stick to the facts. The first sentence of the abstract of this paper asked whether “the provision of sufficient basal insulin to normalize fasting plasma glucose levels may reduce cardiovascular events.” The results of the trial tell us that the answer is simply “No.”
How did you read the ORIGIN trial? What’s your take on the facts versus the spin?
June 19th, 2012
C3 (Complex Cardiovascular Catheter Therapeutics) 2012
Aaron C. Earles, DO
Greetings from Orlando, Florida! I am in town for the C3 therapeutics global summit being held at the Rosen Shingle Creek Resort. This afternoon had some very interesting topics for interventionalists and fellows-in-training. I attended a preconference symposium, Imaging: Moving Beyond Angiography.
Throughout the first year of fellowship, I recall multiple cases where angiography alone failed to show how critical coronary artery stenosis can be. I found the information provided today to be very high yield, especially for those in training. For example, I have used intravascular ultrasound (IVUS) several times this past year, and the presenters did an excellent job discussing the essentials of IVUS interpretation. The symposium also covered fractional flow reserve in great detail. A panel of cardiologists discussed FFR evaluation of special lesions, including LM, tandem lesions, non-LM bifurcation, diffuse disease, and SVG. A discussion on interpretation of optical coherence tomography (OCT) followed. I learned a great deal as I had not seen this technology used before in a live cath lab setting.
A live case transmission from the Sanjay Gandhi Postgraduate Institute for Medical Sciences in Lucknow, India, concluded the session. The case was a patient with triple vessel disease including a CTO LAD lesion, an ostial and mid Cx stenosis, and a PDA stenosis. The cardiologist on the case chose to perform PCI to the CTO lesion, but the amazing part is that he crossed using a retrograde technique via a diagonal collateral! The physicians implemented both IVUS and OCT in this case, which made for a great review of their respective uses. A very interesting case indeed!
After a break for dinner and a reception, I attended Innovation in Endovascular Technology in the Treatment of Peripheral CTOs. I was fascinated by the ingenuity used to open some of these complex peripheral CTO lesions. Methods of CTO crossing via subintimal recanalization versus true lumen crossing as well as new tools and techniques were discussed.
Tomorrow promises to be another great day of topics. I will keep you posted!
June 19th, 2012
Is Chronic Kidney Disease a CHD Risk Equivalent?
Larry Husten, PHD
A study published in the Lancet provides new data about whether chronic kidney disease (CKD) should, like diabetes, be considered a coronary heart disease (CHD) risk equivalent.
Marcello Tonelli and colleagues analyzed data from a population of 1.25 million people in Alberta, Canada. During a median follow-up of 4 years, 11,340 people were admitted to the hospital for MI. People with a previous MI were at higher risk for MI admission than people with either diabetes or CKD:
- MI history: 18.5 per 1000 person-years (CI 17.4–19.8)
- Diabetes: 5.4 per 1000 person-years (5.2–5.7)
- CKD: 6.9 per 1000 person-years (6.6–7.2)
After adjustment for other variables, the relative rate of MI was lower in the CKD group than in the diabetes group (rate and adjusted relative rate for MI admission):
- Previous MI: 7.7%, RR 3.8 (CI 3.5-41)
- Diabetes and CKD: 6%, RR 2.7 (2.5-2.9)
- CKD: 2.8%, RR 1.4 (1.3-1.5)
- Diabetes: 2.4%, RR 2.0 (1.9-2.1)
- No diabetes or CKD: 0.5%, RR 1 (reference)
The authors write that their “data show that diabetes alone and chronic kidney disease alone … do not increase the rate of myocardial infarction to the same extent as does a history of coronary disease, and therefore do not support the use of the term coronary heart disease risk equivalent for either disorder.” However, they conclude that CKD should “be added to the list of criteria defining people at highest risk of future coronary events.”
In an accompanying comment, Tamar Polonsky and George Bakris write that “despite negative findings for the primary outcome, compelling reasons are provided to consider lipid-lowering therapy in patients with chronic kidney disease.”
June 19th, 2012
New Uses Found for a Traditional Walking Test
Larry Husten, PHD
The 6-minute walk test (6MWT) can improve risk prediction in people with stable coronary disease, according to a new study published in the Archives of Internal Medicine. The 6MWT may also be cost-effective and — and may help physicians motivate their patients to exercise, suggest the authors.
Alexis Beatty and colleagues performed a 6MWT and a treadmill exercise test in 556 people with stable coronary heart disease. After a median follow-up of 8 years, cardiovascular (CV) events had occurred in 39.2% of the study participants.
Compared with people in the highest quartile of walking distance (544-837 m), people in the lowest quartile (87-419 m) had four times the risk for a CV event during follow-up.
- Unadjusted hazard ratio: 4.29, CI 2.83-6.53, p<0.001
After adjustment for other factors, each 104-m decrease in walking distance (1 standard deviation) was associated with a 30% increase in CV events (HR 1.30,CI 1.10-1.53). The 6MWT was similar to the treadmill exercise test in predicting CV events.
The authors write that treadmill testing is still preferable for evaluating patients with suspected ischemia, but they note a number of advantages to the 6MWT in stable patients:
The 6MWT can be conducted with little equipment other than a hallway marked for distance and a stopwatch. Due to the self-paced nature of the test, adverse events of chest pain, dyspnea, or musculoskeletal pain are usually mild; serious adverse events have not been described. Furthermore, the 6MWT is less expensive than treadmill exercise testing, especially if stress testing is bundled with imaging that may be unnecessary.
Furthermore, the 6MWT can be used to motivate patients to exercise:
Despite evidence demonstrating the efficacy of exercise-based rehabilitation in patients with CHD for reducing mortality, most patients do not participate in cardiac rehabilitation or achieve recommended levels of physical activity. There is a need for improved strategies to identify patients at the greatest risk of cardiovascular events and to motivate patients and physicians to address physical activity as a modifiable risk factor. Repeated measurement of the 6MWT could be used as a simple office-based tool to monitor exercise capacity and motivate patients to achieve appropriate levels of physical activity. Although we demonstrated that the 6MWT can predict cardiovascular events in stable CHD, its use for improving prognosis merits further study.
In an accompanying comment, David Nash agrees with the investigators and recommends “that physicians interested in improving their patients’ level of fitness use the 6MWT as a means of getting the patient started on regular exercise. Once the patients become familiar with the ease and safety of the 6MWT, they can be encouraged to repeat the 6MWT more frequently, even on a daily basis. It is then possible to lengthen the walk at appropriate intervals.”
June 18th, 2012
Sexual Outcomes Following an MI: Let’s Talk About Sex, Doc
Emily M Abramsohn, MPH
Today, most patients survive an MI. People live after an MI not just to leave the hospital, but to go home, resume work, play sports, and sometimes even enjoy life more. What about sex? Did you know that most patients who have an MI were sexually active in the year prior to the event? And many patients resume sexual activity within a month of discharge from the hospital. Sex after an MI is not without problems. Fear is a major issue that can inhibit patients and their partners from initiating sexual activity. Many couples worry that sexual activity could trigger another MI or even result in death.
The evidence-base for long-term sexual outcomes after MI is scarce, especially for women. Our research on sex after an MI for the TRIUMPH Study, a national, multisite, longitudinal study that followed patients for one year following an acute MI, was recently published in the American Journal of Cardiology. In this study, we looked at patient-physician communication about sex following an MI and predictors of “loss of sexual activity,” or less frequent or no sexual activity following an MI. Additionally, it was the first study to prospectively evaluate, in a large population of men and women with MI, the association between sexual activity in the month after an MI and 1-year mortality. If people have sex soon after an MI, are they any more likely to die in the first year after the MI?
Many men and women were sexually active both in the year leading up to and following the MI, yet few reported receiving discharge instructions about resuming sex. Men and women who did not receive instructions were more likely to report a loss of sexual activity at 1 year, even when controlling for demographic and other health variables. Additionally, while limited by a small number of deaths, 1-year mortality was similar in those who reported having sex in the month following the MI and those who were inactive.
| Gender-separate models predicting of loss of sexual activity | ||
|
Females RR (95% CI) |
Males RR (95% CI) |
|
| Age (10 yr.) |
0.98 (0.84-1.15) |
1.05 (0.89-1.25) |
| Did not receive instructions |
1.44 (1.16-1.79) |
1.27 (1.11-1.46) |
| Discussion with doctor |
0.99 (0.78-1.26) |
1.16 (1.04-1.29) |
| Married at baseline |
0.80 (0.62-1.03) |
0.97 (0.83-1.14) |
| Depressed at baseline |
0.88 (0.72-1.09) |
1.14 (0.88-1.47) |
| Physical function* |
1.08 (0.98-1.19) |
1.17 (1.10-1.24) |
| MI severity^ |
1.00 (0.83-1.20) |
1.10 (0.93-1.30) |
| CI = Confidence Interval; RR = Relative Risk*Physical function was measured using the SF-12 Physical Component Score^MI severity was measured using the GRACE 6-Month Risk Score | ||
Sexual activity is an important factor in the health and quality of life of middle-age and older adults.
How often do you talk to your patients about sexual activity after an MI?
Do you reassure patients about the condition of their heart and explain when sex is safe to resume?
Do you talk to patients about possible sexual side effects, or lack thereof, of medications you prescribe?
Do your patients understand what kinds of symptoms during sexual activity would be a reason to stop having sex and check in with you?
Doctors seem to avoid the topic with women more than with men. Do you tend to avoid the topic of sex with female patients? Your older patients? Patients who are not married? There is no evidence that profiling patients based on these factors is a good way to identify who is and is not interested in sex after an MI. Here are some tips for talking about resuming sexual activity after an MI:
1) Don’t profile. Our study shows that patients who are female or single are less likely to have a doctor talk to them about sex, even if they are sexually active. Single patients may be hoping to find a new sexual partner. There is no good evidence that sociodemographic characteristics are a good way to know which patients are interested in sex.
2) Talk to patients before they go home from the hospital. This is a teachable moment. It may feel like too much information, but even if the patient is not interested at the moment, you are signaling to her/him that this is a reasonable topic for future discussion. They will remember that you mentioned this topic.
3) Patients trust their cardiologist first and foremost to know what is safe for their heart and they want to hear the recommendation about sex and other activities from the treating cardiologist. Don’t turf this issue to someone else on the team, especially the first time it’s addressed.
4) The American Heart Association recently published new guidelines regarding sexual activity and cardiovascular disease. These guidelines state that sex is reasonably safe soon after MI in stable, asymptomatic patients who can withstand mild physical activity.
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