April 1, 2008

Telmisartan, Ramipril, or Both in Patients at High Risk for Vascular Events.

ONTARGET Investigators, Yusuf S, Teo KK, Pogue J, Dyal L, Copland I, Schumacher H, Dagenais G, Sleight P, Anderson C.   N Engl J Med.   2008 Apr 10;358(15):1547-59

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Internal Medicine for Nephrologists
  • M. Parmar

    See these slides for some additional thoughts on the interpretation of combination therapy in the ONTARGET study

    Click here

    Posted on behalf of:

    M. Parmar, MB, MS, FRCPC, FACP, FASN
    Timmins, ON

    Associate Professor,
    Northern Ontario School of Medicine
    Assistant professor, University of Ottawa
    http://www.nt.net/~atbeat

  • David Naimark

    Sorry about the lateness of this reply! Our group at Sunnybrook Hospital in Toronto reviewed the Lancet article in our journal club only recently.

    A few points about the study need to be raised, in our view. The first is with regard to figure 2 which, to the casual observer, would indicate a much more rapid deterioration in GFR for patients on combination therapy compared to single agents. However, the figure is misleading because the x-axis scale is not linear, the six-week tick mark should be much further to the left and the study-end tick mark should be much further to the right (at a median of 56 months). If the scale had been properly presented, one would see an initial sharp drop in GFR (which is to be expected with the reduction in intra-glomerular capillary pressure associated with RAS blockade) followed by a very gradual decline in GFR that would be parallel in the three groups and which would be considerably less than the 1 ml/min/year drop in GFR expected in the healthy general population [see Hemmelgam et al Kid Int (2006) 69, 2155–2161].

    The second concern is the choice of doubling-of-creatinine as an outcome, particularly when subjected to a time-to-event survival analysis. The latter type of analysis assumes that the event of interest is a permanent condition. It makes little sense to perform a survival analysis on a temporary outcome unless one is interested in the time-to-first-occurrence of the condition (which is not of interest in the current context). A doubling of creatinine can easily occur when patients on RAS blockade become volume contracted which then reverts to baseline upon repletion. Worse, that situation would be expected to occur more frequently with combination therapy than with a single agent. The transient nature of the doubling can be seen in table 2 where many more patients suffered the latter outcome than went on to chronic dialysis.

    The third issue, which has been raised by other commentators in this forum, is the very small absolute risk increase with combination therapy versus single agents.

    Finally, as shown in table 3, the baseline, mean urinary albumin to creatinine ratio in all three groups was roughly 0.8 mg/mmol. This means that very few of the patients enrolled in the study had significant proteinuria. It would be a mistake to extrapolate the results of this study to the heavily proteinuric patients that nephrologists consider for combination therapy. We think that a fair conclusion from the study is that combination therapy does not appear to be beneficial beyond single agents in non-proteinuric patients at risk for vascular outcomes.

    One conclusion that nephrologists can take back to the clinic is that RAS blockade, either with single agents or in combination, appears to be very safe. Beyond that, after discounting the COOPERATE results, our group relies on the results of the meta-analysis by Jennings et al [Diab Med 2007; 24: 486 - 493] which demonstrates that combination therapy is more effective than single agents in reducing proteinuria. The latter conclusion is also borne out by the ONTARGET renal outcomes paper.

  • Jo Lee

    In my opinion the ONTARGET study was a well powered mult-centered RCT but done in the wrong pt population.

    As a nephrologist, we use both ACEI/ARB therapy in our most difficult nephrotic pt.

    This study did not describe who was nephrotic, most were not DM’s, and most has no proteinuria.

    Though the endpoints were reached more in the ARB/ACEI group (numbers to HD, doubling scr, mortality), the absolute numbers were not impressive between groups and probably wouldn’t have been significant if not for the very large study population.

    A telling sign that this study was done in the wrong pt population was the number of people on CHRONIC HD at the end of the study (about 30 in each of the three groups, a very small number and not significant). Why would you use an ACEI AND an ARB in vasculopaths who are not DM’s and most w/o proteinuria w scr’s below 2.0?

    If they would only do a study like this in nephrotic pt’s w GFR< 30!!!!

    This study will not at all change how or why I use both ACEI/ARB therapy. If anything, this study proved to me that ACEI/ARB thearpy is well tolerated and DOES DECREASE PROTEINURIA MORE THAN USED INDIVIDUALLY.

  • Visitor

    As a result of the COOPERATE study, I have felt some confidence in using combination ACE inhibitor and ARB in patients who are highly proteinuric.

    Now that the ONTARGET renal outcomes http://www.thelancet.com/journals/lancet/article/PIIS0140673608612362/abstract have been published and that the COOPERATE study http://www.thelancet.com/journals/lancet/article/PIIS0140673603122295/abstract is under some suspicion http://www.thelancet.com/journals/lancet/article/PIIS0140673608606819/abstract, I am more hesitant to utilize this therapeutic strategy. I have to admit I am tending to try supratherapeutic doses of either an ACE inhibitor or ARB instead of combining the two.

    What are others doing?

  • Visitor

    Good evening

    In our practice here , because of our limited infrastructure, nephroprotection is critically important for us . In fact, the combination of ACEi and ARB (such as telmisartan) is not new, and we have applied it in our practice for the past 3 years.

    Our observations:

    1st- that nephroprotection with combination therapy (ACEi and ARB) is better , but the combination of any of them with beta blocker is better.
    2nd – the use of any of these drugs in stage 4 -5 CKD can be associated with deterioration in renal function .
    3rd – telmisartan may make a difference because it has a nephroprotective effect not related to RAS blockade , and
    4th- the addition of a statin to these drugs provides a significant additive nephroprotective effect .

  • Visitor

    The results of this study are of significant concern to me. I have to admit, I have been using a lot of combination ACE inhibitor + ARB therapy in patients with glomerular disease and significant proteinuria. Is anyone concerned about continuing this practice?

  • Daniel Schwartz

    Please share your thoughts about this paper and it’s impact on Nephrology practice.