August 5th, 2013
Deja Vu All Over Again: Study Links Calcium-Channel Blockers to Breast Cancer
Larry Husten, PHD
A new observational study raises the possibility that calcium-channel blockers (CCBs) may be associated with a higher risk for breast cancer. Although previous studies examining this relationship have failed to turn up convincing evidence of a link, the authors of a paper published in JAMA Internal Medicine state that their study is the first to look at long-term use of CCBs in a contemporary population.
Christopher Li and colleagues analyzed data from women in the Seattle area, including 880 women with invasive ductal breast cancer, 1,027 with invasive lobular breast cancer, and 856 controls with no cancer. They found that women taking other antihypertensive drugs, including diuretics, beta-blockers, and angiotensin II antagonists, had no increased risk for breast cancer. But women taking CCBs had significantly elevated risk for ductal breast cancer (OR 2.4, CI 1.2-4.9, p=0.04) and lobular breast cancer (OR 2.6, CI 1.3-5.3, p=0.01). The results were consistent for different types of CCBs.
In an accompanying editorial, Patricia Coogan writes that the study “provides valid evidence supporting the hypothesis that long-term CCB use increases the risk of breast cancer.” As CCBS are the ninth most commonly prescribed drug class in the U.S., “the hypothesis has significant clinical and public health implications.” However, she writes, the results do not mean long-term use of CCBs should be discontinued, “because these data are from an observational study, which cannot prove causality and by itself cannot make a case for change in clinical practice.” On the other hand, the results should not “be dismissed as random noise emanating from an observational study.” She writes that “it is important that efforts be made to replicate the findings.”
One hypertension expert with very long experience in this area is Franz Messerli. In response to my questions, he noted that “there is virtually no antihypertensive drug or drug class that not has been associated with cancer at one time or another.” In particular, CCBs were at the center of a heated debate in the 1990s that was ultimately resolved by the ALLHAT trial, which found no suggestion of an increased risk of cancer associated with CCBs.
One possible source of confusion, Messerli pointed out, is that “hypertensive patients see physicians more often, particularly when their hypertension is more severe as to require CCB therapy. Frequent physician visits increase the odds of cancer diagnosis.”
August 5th, 2013
Faint PRAISE: 13-Year Delay in Publication of a Major Clinical Trial Sparks Criticism
Larry Husten, PHD
Thirteen years after first being presented, the results of the PRAISE-2 trial finally have been published in JACC: Heart Failure. The trial itself is now largely irrelevant to current clinical practice, as the hypothesis it tested has long been abandoned, but the long delay in publication may serve to bring even more awareness to the issue of the delay or complete absence of publication of many clinical trials.
An accompanying editorial, by Marc Pfeffer and Hicham Skali, is highly critical of the delay:
Although standards for conduct and reporting of clinical trials have improved since 2000, the failure to fully vet the results of a clinical trial of human volunteers in a peer-reviewed journal was and remains unacceptable.”
PRAISE-2 had its origins in the first PRAISE trial, which was first presented in 1995 and subsequently published in the New England Journal of Medicine in 1996. In that trial there was no difference between amlodipine (Norvasc, Pfizer) and placebo in the rate of mortality or cardiovascular hospitalization in patients with heart failure. However, a prespecified subgroup analysis turned up the highly surprising result that heart failure patients with a nonischemic etiology who received amlodipine had a highly significant 46% reduction in the risk of death compared with placebo patients.
This subgroup analysis was the basis for PRAISE-2, which had a similar design to PRAISE but only included patients with nonischemic heart failure. As first reported in 2000, and now in JACC Heart Failure, there were no significant differences between the groups in PRAISE-2. The trial therefore failed to confirm the promising observation from PRAISE. Citing additional examples of this phenomenon, Pfeffer and Skali write that PRAISE-2 is a
…prominent example in cardiovascular medicine in which a significant p value for an important irrefutable endpoint such as all-cause mortality from a secondary analysis was not confirmed by a more definitive randomized controlled trial directly testing the hypothesis generated from the initial study…”
The editorialists praise the PRAISE investigators for “promptly conducting the definitive trial to test the hypothesis generated from the subgroup analysis from the first PRAISE trial” but go on to write that “equally deserved is the criticism regarding the 13-year incubation between the completion of the trial with neutral results” in 2000 and the “long overdue first publication of the results.”
It should be noted that Milton Packer, the principal investigator of both PRAISE studies, was also the PI for the REVIVE trials, the results of which were published in April, also in JACC Heart Failure, after a 7-year delay. REVIVE found that although intravenous levosimendan provided symptomatic relief to patients with acute decompensated heart failure, it was associated with an increased risk of adverse cardiovascular events.
In an accompanying editorial about REVIVE, Robert Califf writes that the cardiovascular community “should rejoice in the fact that the REVIVE investigators have finally decided to come out of the data cellar.” He discusses an earlier published subgroup analysis from REVIVE that “advanced the claim that levosimendan is cost effective compared with standard care.” He goes on to comment:
The publication of a non–pre-specified subgroup analysis without first making available the full trial results in a peer-reviewed venue constitutes an example of a publication fostered by commercial interests without appropriate academic participation.”
I asked Packer to respond to the two editorials. He pointed out that he “could have avoided the ‘criticism’ by not publishing at all. But,” he continued:
in reality, it really isn’t criticism; both are simply trying to make a good point. Regarding the reason for the delay, I have no excuse. The usual stuff. There is always something else to do.”
August 5th, 2013
Selections from Richard Lehman’s Literature Review: August 5th
Richard Lehman, BM, BCh, MRCGP
CardioExchange is pleased to reprint this selection from Dr. Richard Lehman’s weekly journal review blog at BMJ.com. Selected summaries are relevant to our audience, but we encourage members to engage with the entire blog.
BMJ 3 Aug 2013 Vol 347
Severe Hypoglycemia and CV Disease: Last week I pointed you to new evidence that repeated hypoglycaemia can lead to increasing hypoglycaemia unawareness, and that it is also strongly associated with cognitive decline. Here is a meta-analysis of observational studies which also demonstrates that severe hypoglycaemia is associated with an approximate doubling of cardiovascular events in patients with type 2 diabetes. Be very careful when prescribing sulfonylurea drugs and insulin to older diabetics. Ignore QOF targets, and think of your patient.
August 1st, 2013
Ask the Experts: Low SCD Incidence Among High School Athletes
William O Roberts, MD, MS, Steven D Stovitz, MD, MS and Erica Sarah Spatz, MD, MHS
CardioExchange’s Erica Spatz asks William O. Roberts and Steven D. Stovitz about their research, published in JACC, on the incidence of sudden cardiac death among high school athletes in Minnesota.
THE STUDY
Researchers retrospectively assessed the incidence of sudden cardiac death (SCD) during Minnesota State High School League (MSHSL) games and practices. Among nearly 4 million athletes (age 12–19; 55% boys) who were screened every 3 years using a state-approved preparticipation examination (PPE) form, 4 SCDs occurred, all in boys (2 during cross country, 1 during basketball, 1 during wrestling). The overall incidence of SCD was 0.24 per 100,000 athlete-years during a period of 19 years.
THE INTERVIEW
Spatz: You found a very low incidence of SCD among high school students in Minnesota who were screened using a state-approved PPE form. What are the implications of these findings?
Roberts and Stovitz: The Preparticipation Physical Evaluation Monograph cited in our study is the work of 6 organizations, including the American College of Sports Medicine, the American Academy of Family Physicians, and the American Academy of Pediatrics. It uses the 12-point cardiovascular preparticipation screening question set from the American Heart Association and the participation recommendations from the current Bethesda Guidelines. The question set for the Minnesota standardized form is used statewide by all health professionals who do the exams. The Minnesota form is reviewed and updated annually by the MHSHL Sports Medicine Advisory Committee to reflect the most recent changes. Notably, the questions on the form have not been derived from or subjected to scientific scrutiny; they are based on expert opinion.
The implications of our findings are fourfold: First, this long-term cohort of high school athletes screened every 3 years with a standard PPE form had a very low rate of SCD during activities for which they were screened. Second, this type of form, if used nationwide, may be effective in screening for SCD at the high school level (with some caveats we discuss below). Third, high school level athletes may be at less risk than college and older athletes, so we should focus research efforts on narrower age ranges than the broad categories of <30–35 and >35–40. Fourth, we found that most high school athletes participate in 2 to 3 sports each year, at least in Minnesota.
Spatz: Describe the Preparticipation Physical Evaluation Monograph. Which groups or risk factors might prompt further diagnostic workup, including an ECG?
Roberts and Stovitz: The PPE Monograph is a comprehensive look at athlete preparticipation issues, including the cardiovascular exam. It focuses mainly on competitive athletes age 12 to 25 but does extend to older and younger athletes.
The cardiovascular questions are grouped into two important areas: “Heart Health Questions About You” and “Heart Health Questions About Your Family.” Other questions address asthma, concussion, musculoskeletal problems, eating issues, and other matters of concern for athletes and parents. The provider is also prompted to address depression, drugs, tobacco, alcohol, sex, and risky behaviors that are not likely to be disclosed by adolescent athletes on a form signed by a parent.
With respect to the cardiovascular questions, a “yes” or positive response should initiate a set of secondary questions outlined in the monograph; in most instances, the athlete is moved on to a case-finding cardiovascular evaluation starting with an ECG. The monograph addresses the educational gap in interpreting findings such as syncope, which may be misinterpreted as a neurologic sign or even ignored.
Spatz: Why do you think you found lower rates of SCD in your study than in previously studied populations (e.g., Italian athletes and NCAA athletes)?
Roberts and Stovitz: Both the Italian and NCAA data sets include older athletes, and some cardiac problems manifest in older athletes. The intensity of training and activity is likely greater in the NCAA (especially Division I) and in young-adult athletes. Also, the genetic predisposition to some cardiac problems may differ among Italian athletes, U.S. college athletes, and Minnesota high school athletes. Also note that our study does not address all the exercise-related cardiac deaths in this age group, only the incidents that met the cardiovascular criteria for catastrophic insurance payments.
Spatz: Should your results, based on high school students in Minnesota, be generalized to other high school populations?
Roberts and Stovitz: We do not think the data can be extrapolated to all U.S. high school athletes, primarily because Minnesota has a lower proportion of African Americans than many other states and a larger proportion of people of northern European heritage. Given that African Americans have a higher rate of hypertrophic cardiomyopathy and SCD than European Americans, SCD rates among high school athletes in other states may be higher. We encourage other researchers to evaluate how states with different ethnic and racial mixes compare with Minnesota. In addition, it would be interesting to see how our data compare with those from states that require PPEs each year or every other year rather than every third year. Given that an increasing number of high school–age athletes now compete for club teams rather than their high schools, future research may need to account for club sport participation. Finally, the spectrum of sports participation in Minnesota may differ from that in other states, even though the average intensity of activity is likely to be similar.
JOIN THE DISCUSSION
Do these data from Minnesota change your thinking about SCD incidence among high school athletes and about how they should be screened before participating in sports?
July 31st, 2013
European Heart Guidelines Based on Disgraced Research May Have Caused Thousands of Deaths
Larry Husten, PHD
Despite a 2-year-old scandal discrediting key evidence, current guidelines relying on this evidence have not been revised. As a result of physicians following these guidelines, some researchers say, it is possible that thousands of patients may have died each year in the U.K. alone. It is unlikely that a true understanding of the damage will ever be known.
Current European Society of Cardiology guidelines recommend that beta-blockers be given to many patients having surgery for noncardiac reasons to protect the heart during surgery. (U.S. guidelines are somewhat less aggressive in their endorsement of perioperative beta-blockade.) The guidelines, which were published in 2009, were based on analyses of the available trials. The strongest evidence came from the DECREASE family of trials, which appeared to strongly support perioperative beta-blockade, and one other large trial, POISE, which raised concerns that beta-blockers might lead to an increase in deaths. When the ESC committee combined all the data, they found a neutral effect on mortality but a strong benefit due to significant reductions in non-fatal MI and stroke with beta-blocker use. This was the basis for the strong recommendation in the ESC guidelines.
In 2011, however, faith in the reliability of the DECREASE trials was shattered as a result of a scientific misconduct scandal centering on the principal investigator of the studies, the now disgraced Dutch researcher Don Poldermans. The issue was further complicated because, in addition to his key role in the trials, Poldermans was the chairman of the committee that drafted the guidelines.
Now, a group of U.K. researchers, led by Darrel Francis, have published in the journal Heart the results of a meta-analysis of the remaining non-DECREASE trials that tested perioperative beta-blockade. With the removal of the DECREASE trials, the findings were strikingly different from the earlier analyses. In a combined population of 10,529 patients taken from nine trials, there was a statistically significant increase in the risk for death in the group randomized to beta-blockers:
- 162 deaths in 5264 patients randomized to beta-blockers versus 129 deaths in 5265 patients randomized to placebo, for a 27% increase in the risk for death (RR 1.27, CI 1.01- 1.60, p=0.04).
In sharp contrast, the two randomized placebo-controlled DECREASE studies found a 58% reduction in mortality associated with beta-blockers (although this was not statistically significant).
The analysis did find some benefits associated with beta-blockade, including a statistically significant reduction in non-fatal MI. However, it also found a significant increase in hypotension and stroke. In the new meta-analysis, any beneficial effects are clearly overshadowed by the most important finding of an increased risk for death.
Each year in the U.K., according to the Heart authors, 2.5 million procedures are performed for which this treatment is recommended in the current guidelines. Based on a 27% increase in the risk for death associated with perioperative beta-blockade, they calculated that as many as 10,000 deaths might be caused by physicians faithfully following the guidelines. In an interview, Francis said that there is no way to reliably assess the true extent of the possible damage, either in the U.K. or elsewhere. The estimate of 10,000 deaths is based on the limited available data.
The Heart authors concluded:
Patient safety being paramount, guidelines for perioperative β-blocker initiation should be retracted without further delay. Future guidelines should be accompanied by a commitment from named individuals to retract them immediately if the advice given is later revealed to be harmful.
Routine initiation of β-blockers for this indication should not be recommended, except in the context of RCTs which should be designed carefully, conducted honestly and reported truthfully.
The chair of the ESC Clinical Practice Guidelines Committee, Jose Luis Zamorano, said that the ESC is currently revising the guidelines, with a new version expected in the first months of 2014. He said the ESC was taking the meta-analysis “very seriously” and would “convene an urgent task force to decide whether further actions are required.”
The new meta-analysis is “interesting but not surprising,” said Sripal Bangalore, the author of a 2008 meta-analysis that raised early questions about both the European and U.S. guidelines. He said the paper is concordant with the POISE trial and his own meta-analsysis. He said it was “difficult to prove” the estimates of the number of deaths that may have been caused by the guidelines.
Leslie David Hillis, the chair of the ACCF/AHA CABG guidelines, said that the Heart paper data and conclusions were “accurate” and that the findings were potentially important.
Sanjay Kaul said that he generally agreed with the conclusions of the Heart paper that the evidence does not support strong recommendations for perioperative beta-blockade, but he said that “the mortality evidence against beta-blockade is not robust.” In his own practice, he said, he does “not initiate beta-blockers to modify perioperative risk even in high-risk patients. I also do not hold beta-blockers prior to surgery in those who are on them long term.”
Mariell Jessup, speaking on behalf of the American Heart Association, said that she thought “the issue of how we use beta-blockers in the perioperative period is very complex and probably requires more trials, irrespective of what we think of some of the trials in the past, and requires great care as we move forward.” She said this issue was now the subject of intense discussion by the joint ACCF/AHA guidelines committee.
Some defenders of perioperative beta-blockade have argued that although initiating beta-blockers on the same day as surgery may be dangerous, a slow and gradual introduction of the drugs for as long as 30 days before surgery may be beneficial. However, according to Francis, this strategy has never been tested in a clinical trial outside of the DECREASE family. In addition, even if this strategy proved safe, it would likely not be feasible in most cases, since perioperative beta-blockade falls under the purview of the anesthesiologist, who generally first sees the patient on the day of the procedure.
July 30th, 2013
More Bad News for Valsartan
Larry Husten, PHD
In the last few days, more bad news about valsartan (Diovan, Novartis) has emerged. Another major study conducted in Japan — the Jikei Heart Study — will be retracted, and Japanese health authorities said they were investigating severe skin reactions associated with use of the drug.
The new events are only the latest problems for the drug and Novartis. As reported previously, the current scandal first began to unfold in late 2011 when a Japanese blogger pointed to a number of apparent errors in publications authored by Hiroaki Matsubara. This ultimately led to a series of retractions of Matsubara papers and the retraction of the main paper of the Kyoto Heart Study itself. In February, Matsubara resigned his position at Kyoto Prefectural University of Medicine. Earlier this month, the Japanese health minister and officials at Kyoto Prefectural University of Medicine said that data from the Kyoto Heart Study had been fabricated.
Now a second large trial, the Jikei Heart Trial, will also be retracted. Questions had been raised earlier about this trial when it became known that Novartis employees had worked on both the Kyoto and the Jikei trials. The relationship of the employees to the company was not disclosed in the trial publications. Now, as reported in Pharmaceutical Processing, the first author of the Jikei Heart Trial, Seibu Mochizuki, has said that the trial, originally published in the Lancet in 2007, will be retracted.
Novartis said that an independent investigation found no evidence that its employee who worked on the trial manipulated or altered the data. An official at Jikei University School of Medicine said that its own investigation had not ruled out such misconduct on the part of the former Novartis employee. The employee has denied such wrongdoing.
The Jikei investigation found that the blood pressure data used in the Lancet paper were different from the actual medical records.
In a separate development, the Japan Times reported that the Japanese health ministry was investigating reports of severe skin reactions linked to the use of valsartan.
July 29th, 2013
Selections from Richard Lehman’s Literature Review: July 29th
Richard Lehman, BM, BCh, MRCGP
CardioExchange is pleased to reprint selections from Dr. Richard Lehman’s weekly journal review blog at BMJ.com. Selected summaries are relevant to our audience, but we encourage members to engage with the entire blog.
NEJM 25 July 2013 Vol 369
Riociguat for the Treatment of Chronic Thromboembolic Pulmonary Hypertension and Pulmonary Arterial Hypertension (pages 319 and 330): There are still some life-shortening conditions where there are so few therapeutic options that everybody with them should be invited to take part in randomized trials of new interventions. One such is chronic thromboembolic pulmonary hypertension. Progression leads to reduced walking distance and ultimately to death, and is accompanied by an inexorable rise in B-type natriuretic peptide. So when a drug comes along that leads to an improvement in walking distance and a decrease in BNP over 16 weeks, it could mark a potential breakthrough, though we cannot be certain without longer trials. The drug is riociguat, a member of a new class of compounds, the soluble guanylate cyclase stimulators. The two trials reported here and here are very similar and encouraging. Yet the accompanying editorial contains a pretty explicit warning:
“Another caveat, which is not unique to PATENT-1 and CHEST-1, is the relationship to the sponsoring company. The study was supported by Bayer HealthCare, and although the manuscript was drafted by the first author, editorial assistance was provided by a company supported by the sponsor (Adelphi Communications). In addition, although the authors had access to the complete database, the statistician was employed by Bayer HealthCare. Riociguat is poised for examination by the Food and Drug Administration as a therapy for pulmonary hypertension and, if approved, has the potential to generate substantial revenue for the sponsor. In light of the financial stakes, both real and apparent investigator autonomy remain key to ensuring the delivery of new drugs for pulmonary hypertension for patients.” So where does the buck stop—with the NEJM which printed these studies, and will presumably get reprint income from Bayer, or with the FDA? Which impartial body is going to conduct the necessary replication studies and long-term mortality studies? Do we get to see the full data set?
Mechanisms of Hypoglycemia-Associated Autonomic Failure in Diabetes (pg. 362): This week’s NEJM review article is about hypoglycaemia—something that we all need to take more account of when piling on treatments for diabetes. This paper deals with the detail of autonomic regulation of hypoglycaemia awareness, and why awareness tends to diminish with each hypoglycaemic episode. The wider clinical relevance of hypoglycaemia is the subject of a brilliant article by Kasia Lipska and Victor Montori in this week’s JAMA Internal Medicine.
BMJ 27 July 2013 Vol 347
Renal Outcomes Associated with Invasive vs. Conservative Management of ACS: It’s the end of July and there is sleepiness in the air; even people who aren’t on holiday feel as if they should be; e-mails go unanswered, and jobs get postponed. Perhaps this accounts for the lack-lustre contents of the journals at this time of year too. A Canadian register was trawled for evidence that renal outcomes after acute coronary syndrome might be influenced by invasive versus conservative management: they found that early invasive management of acute coronary syndrome is associated with a small increase in risk of acute kidney injury, but not dialysis or long term progression to end stage renal disease.
JAMA Intern Med 22 July 2013 Vol 173
Association Between Hypoglycemia and Dementia in Older Adults with Diabetes Mellitus (pg. 1300): The more you look at what we are incentivized to do with elderly diabetic patients, the scarier it gets. Are we reducing beta-cell decline, or accelerating it? Are we reducing cardiovascular risk, or increasing it? When we tighten control, are we preventing cognitive decline or inducing it? For every treatment beyond metformin, we simply don’t know. But there is increasing evidence that by inducing hypoglycaemia, commonly with sulfonylurea drugs or insulin, we are in danger of damaging the elderly brain, and elderly people with dementia then become more prone to hypoglycaemia. It’s a bidirectional disaster area, as this study shows. In an elderly diabetic cohort followed for 12 years, “those who experienced a hypoglycaemic event had a 2-fold increased risk for developing dementia compared with those who did not have a hypoglycaemic event… Similarly, older adults with DM who developed dementia had a greater risk for having a subsequent hypoglycaemic event compared with participants who did not develop dementia.”
Statins and Musculoskeletal Conditions, Arthropathies, and Injuries (pg. 1318): Statins are great. And the initial randomized trials showed no increase in muscle aches in the treated group. Now that is really strange, because every GP has encountered many patients who are desperate to continue taking a statin but cannot because of muscle pains which recur whenever they do. Nor do we quite know the full range of muscle effects which statins can produce: this retrospective cohort study with propensity score matching concludes that “musculoskeletal conditions, arthropathies, injuries, and pain are more common among statin users than among similar nonusers.” But let’s not get carried away: the odds ratios in the study were pretty small (1.07-1.1).
July 29th, 2013
Sex and the Cardiac Patient Should Not be a Taboo Subject
Larry Husten, PHD
It’s not an easy conversation to have. After a heart attack or other major cardiac event, talking about sex is awkward, and often avoided by patients, their partners, and physicians. But a new consensus statement from several major cardiology organizations urges physicians to get over their reluctance or embarrassment and counsel their cardiac patients about this important, but often neglected, aspect of their lives.
After a patient has a heart attack, stroke, cardiac surgery, cardiac device implantation, or is newly diagnosed with a cardiovascular condition, physicians and other healthcare professionals should provide individually tailored information and advice about a wide variety of issues relating to sexual activity, according to the consensus document developed by the American Heart Association (AHA) and the European Society of Cardiology and published in Circulation and the European Heart Journal. The advice “should address topics such as when to resume sex, specific methods and recommended positions, and the role of intimacy without sex,” said the American Heart Association in a press release.
The statement cites numerous concerns, both psychological and physiological, that patients may have after a coronary event, including “general anxiety, fear of having another MI, feeling unwanted by their partner or not good enough, changes in self-perceptions, inadequate knowledge regarding the impact of heart medications, and finally, partner concerns.”
Most healthcare professionals understand the importance of these issues but do not know what specific advice they should give or when it should be given. They may also be hindered by inexperience and a lack of training, as well as cultural and language barriers. Embarrassment may also play a large role for all the concerned parties. Many heart patients are also elderly, and although sexual activity is by no means absent in this group, it is subject to “stereotypical views on aging and sexuality.” The statement recommends that healthcare providers take a “proactive approach” about sexual concerns and avoid assuming “that sexual issues are of lesser concern to older adults.”
The document addresses many sensitive issues:
Both sexes report fear of intercourse or orgasm after a cardiac event, and often this information is not communicated by the patient to the partner or provider, which leads to stress and possible deterioration of the relationship. Men as partners reported challenges to masculine self-image as a sexual being and hesitancy in approaching their female partners, viewing them as more fragile after MI. Women as partners reported a great sense of loss and uncertainty, both emotional and sexual, related to their male partner with MI.”
The document provides clear advice about assessing risk related to sexual activity. Patients may be relieved to learn that if they do not experience symptoms during an exercise test they are unlikely to experience similar symptoms during sexual activity. Physicians can encourage patients to resume sexual intercourse if they are capable of reaching 3-5 METS on an exercise test:
Sexual activity is often equated with an exercise workload of 2 to 3 METs in the preorgasmic stage and 3 to 4 METs during the orgasmic stage. This is equivalent to walking a treadmill at 3 to 4 miles per hour. This amount of energy expenditure has also been compared to climbing 2 flights of stairs at a brisk pace, although this may not be a useful indicator in those who are older or less physically fit or who have significant CVD. For those with HF, the 6-minute walk test can easily be administered in the clinical setting to assess stability and ability for exertion. HF patients who are not able to manage the 6-minute walk test, or expend ≈3 to 5 METs, may not be able to handle the exertion required for sexual activity. This should be discussed with the patient and partner.”
The documents states that “sexual activity is reasonable” 1 or 2 weeks after an uncomplicated MI if patients do not have symptoms during mild-to-moderate physical activity. Following CABG or other open heart surgery, sexual activity can resume after 6 to 8 weeks.
But, the document notes, “the stress of extramarital sexual activity could pose a health risk for people with heart disease.”
“Patients are anxious and often afraid sex will trigger another cardiac event – but the topic sometimes gets passed over because of embarrassment or discomfort,” said Elaine Steinke, A.P.R.N., Ph.D., lead author of the statement and professor of nursing at Wichita State University in Kansas, in the AHA press release.
“There are many barriers or misconceptions that inhibit discussions about sex. Some healthcare professionals may believe the patient does not want this information, but we have found it is easier for the healthcare provider to start the discussion than for the patient to bring up these issues”, said Tiny Jaarsma, R.N., N.F.E.S.C., co-chair of the task force and a professor at the Linköping University, Sweden, in the press release.
July 29th, 2013
Possible Cognitive Benefits Found in Dementia Patients Taking Centrally Acting ACE Inhibitors
Larry Husten, PHD
An observational study from Ireland raises the intriguing possibility that centrally acting ACE inhibitors may help slow the cognitive decline that is a hallmark of people with Alzheimer’s disease and other forms of dementia.
The study, published in BMJ Open, followed the rates of cognitive decline in 3 groups of patients: dementia patients being treated with centrally acting ACE inhibitors, dementia patients being treated with non-centrally acting ACE inhibitors, and dementia patients newly treated with centrally acting ACE inhibitors.
After six months, there was a significant difference in the rate of decline between the centrally acting ACE inhibitor group and the non-centrally acting ACE inhibitor group in the rate of decline as assessed by the Quick Mild Cognitive Impairment (Qmci) score and a similar but not significant difference in the Standardized Mini-Mental State Examination (SMMSE). This same pattern has been previously observed.
A novel finding, however, was that patients newly treated with centrally acting ACE inhibitors actually had an improvement in their SMMSE scores, compared with declining scores in both groups of patients already taking ACE inhibitors.
The differences in the SMMSE achieved statistical significance, and remained significant after multivariate analysis, though the investigators acknowledged that “the differences were small and of uncertain clinical significance.” However, they speculated that the differences could result in important clinical benefits “if sustained over years.”
The centrally acting ACE inhibitors in the study were perindopril, ramipril, trandolapril, captopril, fosinopril, lisinopril, prinivil, and monopril.
July 25th, 2013
Novel Pulmonary Hypertension Drug Shows Modest Promise in Phase 3 Trials
Larry Husten, PHD
A new drug appears to have promising — but not game-changing — effects in people with two forms of pulmonary hypertension. Riociguat, a soluble guanylate cyclase stimulator under development by Bayer, is thought to have vasodilating, antiproliferative, and antifibrotic effects.
Results of two phase 3, placebo-controlled trials were published today in the New England Journal of Medicine. CHEST-1 studied the clinical impact of riociguat in 261 patients with chronic thromboembolic pulmonary hypertension; PATENT-1 studied the the drug in 443 patients with pulmonary arterial hypertension.
Both forms of pulmonary hypertension are characterized by blockage of the pulmonary vasculature. Patients with pulmonary hypertension are at high risk for right ventricular failure and death. Even though there are now several approved therapies for pulmonary arterial hypertension, the yearly mortality rate remains high, at about 15%. No drugs are approved for chronic thromboembolic pulmonary hypertension, though a surgical procedure, pulmonary endarterectomy, can cure the disease when it is successful. However, pulmonary endarterectomy is a difficult procedure that should only be performed at a very few centers with experience performing the procedure.
In CHEST-1, the primary endpoint of the study, the distance walked in 6 minutes after 16 weeks of treatment, increased by 39 m in the riociguat group, compared with a 6-m decrease in the placebo group (mean difference 46 m, CI 25-67, p<0.001). The investigators also reported that pulmonary vascular resistance decreased in the riociguat group and increased in the placebo group. N-terminal pro-brain natriuretic peptide (NT-proBNP) levels and WHO functional class also improved in the riociguat group. Right ventricular failure occurred in 3% of patients in each group; syncope occurred in 2% of the riociguat group and 3% of the placebo group.
In PATENT-1, the primary endpoint of the study, the distance walked in 6 minutes at 12 weeks, increased by 30 m in the highest-dose riociguat group, compared with a 6-m decrease in the placebo group (mean difference 36 m, CI 20-52, p<0.001). Riociguat was equally effective in patients taking no other therapy and in those taking other drugs. Riociguat was also associated with improvements in pulmonary vascular resistance, NT-proBNP levels, WHO functional class, time to clinical worsening, and Borg dyspnea score. Syncope occurred in 4% of the placebo group versus 1% of the riociguat group.
Exploratory analyses of long-term extension studies– CHEST-2 and PATENT-2– suggested that the increase in walking time associated with riociguat may continue to grow after the initial 12 and 16 weeks of the original trials.
In an an accompanying editorial, Stephen Archer gave a cautious endorsement of riociguat, but noted that the increase in walking distance was modest in both trials. In PATENT-1, the improvement found with riociguat just reached the mark for the smallest beneficial change justifying a change in treatment. The improvement in CHEST-1 was somewhat greater, Archer said, but the expected benefits associated with pulmonary endarterectomy are considerably larger, resulting in a 100-m increase in walking distance instead of the 46-m increase associated with riociguat. He recommended that suitable surgical candidates “should continue to undergo surgery and not be relegated to an inferior treatment.”
Archer concluded:
…the glass may be seen to be half empty because of the modest improvement in 6-minute walk distance with riociguat. However, I view the glass as half full, because riociguat appears to be safe and is a promising addition to the pharmacopeia for Group 1 pulmonary hypertension and potentially the first effective oral therapy for inoperable Group 4 pulmonary hypertension.
Archer discussed another important reason to remain cautious until riociguat undergoes FDA review:
The study was supported by Bayer HealthCare, and although the manuscript was drafted by the first author, editorial assistance was provided by a company supported by the sponsor (Adelphi Communications). In addition, although the authors had access to the complete database, the statistician was employed by Bayer HealthCare.
CardioExchange Associate Editor John Ryan has taken a closer look at the these two trials. Read his analysis and post your comments
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