Search Annals: Advanced search

Podcast Transcript - November 6, 2007

[ Return to Podcast Home Page ]

Hello, and welcome to this week’s Annals of Internal Medicine audio summary for our November 6, 2007 issue. I’m Michael Berkwits, Deputy Editor at Annals.

We have another fabulous issue for you this week, with articles on the comparative effectiveness of ACE inhibitors and angiotensin receptor blockers for treating hypertension and proteinuria; an interview with Dr. Patrick Parfrey on the use of renin-angiotensin inhibitors in patients with chronic kidney disease; the effects of risperidone on symptoms of major depression in patients who don’t respond to initial antidepressant therapy; and the American College of Physicians’ latest practice guideline recommendations on the management of stable chronic obstructive pulmonary disease. And I’ll be summarizing the rest of the articles in this week’s issue.

But first, here’s an in-depth summary of those articles.

Appearing on our annals.org website this week are two meta-analyses, an Agency for Healthcare Research and Quality–funded meta-analysis of the comparative effectiveness of ACE inhibitors and angiotensin receptor blockers, or ARBs, for treating essential hypertension; and a part-industry, part privately funded meta-analysis of studies comparing monotherapy with ACE inhibitors or ARBs to combination therapy with both in patients with chronic kidney disease and proteinuria.

Annals is publishing the analyses on-line, ahead of their appearance in the print journal, as part of a general effort to bring high quality systematic reviews quickly to the research and clinical communities.

In the first of the two studies, lead author David Matchar and his colleagues from Duke University in Durham, NC, looked at 49 clinical trials and 12 other studies that directly compared ACE inhibitors, most often enalapril, and ARBs, most frequently losartan, for the treatment of essential hypertension. Their review had five main findings.

First, there was good evidence that the two drug classes are equivalent in their effects on blood pressure.

Second, there was fair-to-good evidence that ACE inhibitors cause cough more frequently than ARBs.

Third, there was fair evidence that the drug classes are equivalent in their effects on serum creatinine, glomerular filtration rate, and left ventricular mass and function;

Fourth, there was weak evidence that adherence to ARBs is better than that to ACE inhibitors;

And finally, they found insufficient evidence to make any claim about the comparative effects of the two drug classes on cardiovascular events and mortality, or to say anything about the comparative effects of the classes in important clinical subgroups of hypertension, such as patients with diabetes, chronic kidney disease, and heart failure.

On the basis of these findings, the authors conclude that any meaningful differences between ACE inhibitors and ARBs are likely to be small, with the exception that ACE inhibitors are more likely to cause cough. Identifying those differences is likely to require large prolonged studies in generalizable populations and settings, they say, but they acknowledge that the efforts may be justified given that very small potential differences in effects in populations with extremely common conditions may still be significant in absolute effects at the population level.

In the second of this week’s on-line articles, lead author Regina Kunz and her colleagues from the Basel Institute for Clinical Epidemiology at the University Hospital Basel in Basel, Switzerland, looked at 49 randomized trials comparing ACE inhibitors and ARBs alone and in combination for the treatment of nephropathy in patients with proteinuria.

They identified 23 trials which compared an ACE inhibitor to an ARB, 16 which compared both therapies to an ARB, and 23 which compared both therapies to an ACE inhibitor.

Their review of the evidence found that the two drug classes were equivalent for reducing proteinuria, but that the combination of the drugs was better than either one alone, and that the effects were the same across important subgroups of patients, such as those with more or less proteinuria and those with and without diabetic nephropathy. The trials they reviewed did not look at the effects of the interventions on the need for renal replacement therapy, and the trials did a pretty poor job of reporting adverse effects. This is important, the authors claim, because most studies used a highly selected middle-aged population that probably was probably pretty healthy, and that had proven that they could tolerate maximum doses of the drugs, and could take them as prescribed, so that the incidence of hyperkalemia and other complications of therapy is probably much greater in real worl patients than that which is characterized by the literature. For this reason, the author say, the clinical implications of the findings are limited. They suggest that in patients whose proteinuria does not fall below 500 mg daily on either an ACE inhibitor or an ARB, providers might try both if they closely monitor serum potassium and other adverse effects. But the overall safety of that approach in real-world patients needs to be demonstrated before it can be routinely recommended.

In an accompanying editorial, Dr. Patrick Parfrey, a University Research Professor at Memorial University in Newfoundland, Canada, writes that the most important contribution of the reviews is that they tell us what we don’t know, most notably, the rate of progression of chronic kidney disease in terms other than that of proteinuria, and the safety of combination ACE inhibitor and ARB therapy in patients with chronic kidney disease. I spoke with Dr. Parfrey and asked him to review what we know about the drug classes, and to expand upon his comment on drugs safety on what he thought might be the clinical implications of the study findings.

Q: Dr. Parfrey thank you for talking to me.

A: No problem.

Q: Let’s review some of the basics. What’s the difference between ACE inhibitors and ARBs? Physiologically what does the one drug class do that the other doesn’t?

A: Angiotensin 2 is created by the action of angiotensin converting enzyme, and then the angiotensin 2 has an effect on the receptors of the cells. A c;ss of drugs that are inhibitors to that enzyme have been created called the angiotensin converting enzyme inhibitors. In addition, another class of drugs have been created which block the effect of angiotensin 2 on cells, these are called angiotensin receptor blockers. So the drugs interfere with two different parts of the pathway and neither drugs have 100% capacity of inhibiting either the enzyme or the receptor. So the proposal has been that if you actually gave both types of drugs that you would have better inhibition of the renin angiotensin system.

Q: And remind us if you can about how the adverse affects of ARBS compare to those of ACE inhibitors.

A: Well the one adverse effect that’s clearly different between the two classes are cough in the case of ACE inhibitors. It occurs more frequently but in a minority of patients who receive ACE inhibitors. There is no strong evidence that suggests that other side effects are different comparing ARBs to ACE inhibitors.

Q: And it’s still common practice for providers to start one of these drugs and then when they see a bump in creatinine to back off the dose or discontinue the drug altogether. What’s the thinking about that now; is there a creatinine or GFR threshold beyond which any further medication-related change in the measures will do patients more harm than good?

A: The evidence that the inhibitors of the renin-angiotensin system decrease the progression of chronic kidney disease is quite strong. However, in people who have got one functioning kidney which might have a vascular blockage, or even two functioning kidneys that have got a vascular blockage, in which the perfusion of the kidney is dependent on the renin-angiotensin system, there is concern that the use of those agents would decrease the perfusion through those kidneys. In general, in diabetics for instance, there may be a bump in serum creatinine but it should be acceptable as long as it’s probably not 25% greater than that at baseline. So one tends to encourage the use of both of those agents in chronic kidney disease.

Q: So to be clear, if the bump is 25% or less, than that’s considered acceptable and shouldn’t lead to a discontinuation of the drug?

A: Well that would be my opinion, yes.

Q: Now on to the studies. What would you say are the take-home messages from the two reviews this week? A: Well, the one review was looking at the comparative effectiveness of ACEIs versus ARBs in essential hypertension, and the second review was the comparison of those two agents in the prevention of proteinuria or the treatment of proteinuria in chronic kidney disease. But in addition, that particular study examined combination chemotherapy to monotherapy on the reduction of proteinuria. So in the first study, which comes from Duke, they demonstrated comparable antihypertensive effectiveness comparing the two classes of agents. And in the other study from Europe they demonstrated comparable antiproteinuric effectiveness between ACEIs and ARBS. On top of that they demonstrated that combination therapy was better than monotherapy in the reduction of proteinuria. Those findings were probably not unexpected. But these studies demonstrated a lack of evidence in studying the safety of these agents. There are no really big studies examining mortality, for instance, comparing ACEIs to ARBs -- there’s probably only about 3,500 people in comparative studies of those two agents -- and in particular, in examining combination therapy compared to monotherapy, there’s hardly any safety data, which is a big concern. And in particular, if you are treating proteinuria the number of people who would have Class 4 and 5 chronic kidney disease may be large. Those people are a high risk group, they have a high prevalence of comorbidity and they’re prone to hyperkalemia as the glomerular filtration rate drops. So if there was unsupervised utilization of the combination therapy in that group of patients, the likelihood of adverse events occurring particularly due to hyperkalemia would be quite high. We have experience in the introduction of the combination of ACE inhibitors plus spironolactone for the treatment of heart failure. And when that became common practice the number of admissions for hyperkalemia at the hospital increased dramatically. So if you had universal utilization of combination therapy for the treatment of proteinuria without proper monitoring I think the same thing would probably happen. So I think these reviews demonstrated proven antihypertensive and antiproteinuria effectiveness, but unknown safety outcomes, particularly in the long term.

Q: So they sound a note of caution about using combination of ACE inhibitors and ARBs because of the lack of evidence of safety and of longterm outcome.

A: Correct. Both studies suggest that there needs to be randomized controlled clinical trials in which there is head-to-head comparison between ACEIs and ARBs, and in addition there would be a comparison of both those agents used as monotherapy to the combination of ACEIs plus ARBs. And that would need to take place in large numbers of people so that there were enough events that were serious that could allow us to comment on the relative safety of these agents. The indication for combination therapy would be the failure for monotherapy to reduce 24-urine protein less than 0.5 grams, and if someone decides that they want to use combination therapy for the treatment of proteinuria, I think it would be very important to calculate the glomerular infiltration rate because often the low glomerular infiltration rate may not be obvious from the serum creatinine. And if that GFR is below 60 ml/min they need to be very careful about adverse effects, particularly hyperkalemia. Therefore it would be important to monitor hyperkalemia in those patients.

Q: One common recommendation is that providers should reserve the use of ARBs for patients who require ACE inhibitors but who have adverse effects or who are otherwise intolerant of them. Now that these reviews suggest that the drugs are roughly equivalent in their efficacy and that ARBs may cause fewer side effects, can ARBS be considered a reasonable first-line choice equivalent to ACE inhibitors, say for renal protection in patients with diabetes or patients who remain hypertensive on a thiazide diuretic?

A: I think they probably are equivalent and I think that one might make a final decision based on cost. However we are awaiting the long term outcomes of their relative safety.

Q: And while the review comparing the effectiveness of ACE inhibitors and ARBs for hypertension didn’t look at combination therapy, can we tell anything about the benefits of combining those two drug classes for hypertensive patients from the review that looked at proteinuria? Is the combination of ACE inhibitors and ARBs an underappreciated treatment option for hypertensive patients whether or not they have renal insufficiency?

A: The review examined the proteinuria as the outcome and didn’t examine hypertension as an outcome in that group of people. There has been a recent study published in Kidney International called IMPROVE which compared the effectiveness of a combination therapy to monotherapy in 400 patients who had essential hypertension or had early kidney disease they just had low levels of albumin secretion, and they didn’t determine any extra benefit in the combination therapy on proteinuria after 20 weeks. They didn’t demonstrate any difference in safety either. So the conclusion there was that in early stage disease with low levels of albumin secretion, combination therapy wouldn’t be indicated.

Q: Dr. Parfrey thanks so much for talking to me.

A: No problem.

That was Dr. Patrick Parfrey, University Research Professor at Memorial University in Newfoundland, Canada, and an author of an editorial this week accompanying the two meta-analysis of renin-angiotensin inhibitors.

The systematic reviews, entitled “Comparative Effectiveness of Angiotensin-Convetying Enzyme Inhibitors and Angiotensin II Receptor Blockers for Treating Essential Hypertension,” and “Effect of Monotherapy and Combination Therapy with Inhibitors of the Renin-Angiotensin System on Proteinuria in Renal Disease,” are available now at our annals.org website, and will appear in the January 1, 2008 issue of the journal.

Our lead article in the print journal this week is an industry-funded randomized trial looking at the effect of risperidone on major depression.

Risperidone is an atypical antipsychotic approved in the US for treatment of schizophrenia and bipolar disease but also often used for other behavioral, depressive, and anxiety disorders, and an open-label study performed by the same authors in 2006 suggested that it may be a useful addition to standard antidepressant therapy in patients with major depression who have residual symptoms of depression on standard therapy.

In this week’s trial, lead author Ramy Mahmoud and his colleagues from Janssen Pharmaceutica tested that hypothesis in a double-blind trial. They randomized adult patients with major depression who remained symptomatic on standard take risperidone 0.25 mg titrated upward to 1-2 mg, or placebo, in addition to the antidepressants – mainly SSRIs and SSNRIs - for 6 weeks.

The trial had 2 main findings.

First, symptom severity was less and disease remission was more frequent in patients randomized to the risperidone arm, and patients assigned to risperidone reported greater improvements in qualify of life and disability.

Second, more patients assigned to risperidone withdrew from the study because of adverse effects, but most of the effects were nonspecific somnolence and malaise, and there were no significant differences in serious or non-serious events between groups.

On the basis of these findings, the authors conclude that the addition of risperidone to standard antidepressant therapy helps patients with major depression who do not fully respond to standard therapy. The authors acknowledge that the duration of the trial was relatively short; that the trial results can’t help provider choose a specific risperidone SS RI or NRI combination; and that a substantial proportion of patients continued to experience symptoms of depression even with combination treatment. The authors don’t acknowledge a growing pharmacoepidemiologic literature raising questions about the safety of atypical antipsychotics in older patients, and they underplay the fact that risperidone is one of a huge number of next-step options for patients with major depression, several of which were compared directly in the Sequenced Treatment Alternatives to Relieve Depression, or STAR*D trial. Reports of that trial continue to fill the psychiatric literature, and options include switching agents within an antidepressant drug class; adding a second drug from a different antidepressant drug class; adding a second drug that’s not an antidepressant or an atypical antipsychotic, such as buspirone or bupropion; or non-pharmacologic treatment, such as cognitive therapy or electroconvulsive therapy. Nevertheless, Annals editors thought this week’s article was a good attempt evaluate, using a high quality study design, the benefits of one such option in the treatment of depression, a common and often disabling condition seen in primary care patients. Click the “Related information” link accompanying this article at our annals.org site to learn more risperidone and augmentation therapy with psychoactive agents.

Our CME article this week is a systematic review and ACP clinical practice guideline addressing the the diagnosis and management of stable COPD. Lead author Timothy Wilt and his coauthors from the Minneapolis VA medical center and the University of Minnesota structured their review around 5 questions that the College’s Clinical Efficacy Assessment Subcommittee used to develop 6 practice recommendations.

First, the authors asked if screening spirometry is useful for identifying patients who might benefit from treatment, or it could give providers thresholds that clearly indicate when treatment should be started or changed. They identified insufficient evidence that the test was useful in these ways, leading to the guideline recommendation that spirometry should be performed to diagnose airflow obstruction in patients with respiratory symptoms but should not be used to screen for airflow obstruction in asymptomatic people.

Second, the authors asked about clinical and spirometric indications for treatment. They found good evidence that symptomatic patients and those with an FEV1 < 60% of predicted are most likely to benefit from treatment; they found good evidence that those with only mild to moderate obstruction and those with chronic sputum production without obstruction are unlikely to benefit from treatment; and they found fair evidence that using spirometry readings to change treatment is probably not beneficial, and these findings led to the guideline recommendation that treatment should be reserved for patients with respiratory symptoms and an FEV1 < 60% of predicted.

Third, the authors looked for evidence about which inhaled therapies are effective, and the answers varied by outcomes. They found good evidence that monotherapy has no effect on mortality. They found good evidence that long acting inhaled anticholinergics, long acting inhaled beta2 agonsts and inhaled corticosteroids are comparably effective for reducing exacerbations. And they found fair evidence that monotherapy and combination therapy don’t generally improve questionnaire-defined health status, leading to the guideline recommendations to use one of the above 3 inhaled treatments as monotherapy and to consider using combination inhaled therapy for symptomatic patients and those with FEV < 60% of predicted.

Fourth, the authors asked when clinicians should use oxygen, and they found good evidence that when used for 15 or more hours daily and titrated to maintain a Pa02 > 60 mm Hg, oxygen reduced mortality in patients with an FEV1 < 30% of predicted and a mean resting Pa02 55 mm Hg, leading to the recommendation to prescribe oxygen therapy in patients with COPD and resting hypoxemia (Pao2 55 mm Hg).

Finally, the authors asked when clinicians should consider pulmonary rehabilitation and disease management programs. They found evidence that pulmonary rehabilitation improves respiratory symptoms but not exercise capacity, and that disease management programs reduced hospital admissions and improve health status and exercise capacity, leading to the guideline recommendation to consider prescribing pulmonary rehabilitation in symptomatic individuals with COPD who have an FEV1 less than 50% predicted. (Grade: weak recommendation, moderate-quality evidence.)

Susbscribers to Annals can receive CME credits by answering 2 quiz questions about these guidelines. Just go to cme.annals.org and click “My CME” to register, or sign in.

Other articles in this week’s issue include:

A small, short-term randomized trial suggesting that oral phosphatidylcholine may reduce corticosteroid dependence in patients with chronic, steroid-refractory ulcerative colitis;

An observational cohort study using pooled data from the Wegener Granulomatosis Etanercept Trial suggesting that changes in PR3-ANCA levels don’t correlate with disease activity, they have no detectable association with remission and relapse, and should not be used to guide decisions about treatment;

We have a qualitative study of domestic violence screening of women in emergency departments, identifying helpful, empathic screening strategies associated with disclosure of domestic violence, and conversely, awkward and unhelpful questions that are associated with non-disclosure, and we have an accompanying editorial urging the medical community to face its responsibilities to improve provider education, training, and response to domestic violence.

We’re publishing a Position Paper from the Society for General Internal Medicine providing recommendations for teaching about racial and ethnic disparities in health and health care;

We have one of our occasional Trials That Matter editorials about clinical trial published in the BMJ in July, comparing liquid-based to conventional cervical cytology for ccervical cancer screening;

And we have an Update in Hospital Medicine, the 7th of 10 updates appearing this year based on presentations given at the American College of Physicians annual Internal Medicine 2007 session held in April in San Diego.

And, finally, if my droning on and on in this summary has given you a massive headache, then turn to this months’ In The Clinic, which features advice and Tables and recommendations and Clinical Bottom Lines about Migraine.

Well that’s it for today.

For full details of all of this week’s articles, please consult your print journal, or go to www.annals.org.

We’ll try something else new this week. I still don’t know if anyone’s listening to these summaries, or listening to the end, so in honor of our lead article on the lifting of major depression with the use of antidepressants and risperidone, off Yazoo records’ 2000 Best of Blind Blake release, I’ll say goodbye with Arthur Blake from the late 1920’s; here’s The Depression Has Gone From Me Blues.

[Music]

Technical support for this summary was provided by Andrew Langman, Neil Kohl, and Beth Jenkinson.

Special thanks to Kevin Stahl and all our friends at WHYY, public radio and television of Philadelphia, who helped produce these podcasts.

If you love these summaries or if you can’t stand the music, tell me about it, at podcast{at}annals.org.

Check back in 2 weeks for a complete summary of our regularly scheduled November 20, 2007 issue.

I’m Michael Berkwits, and thanks for listening.

[Music]

[ Return to Podcast Home Page ]