Monday, November 17, 2008


Since the second half of this decade, cardiologist have become more aware of the fact that heart failure, as we know it in the nineties, actually have two large varieties, the systolic heart failure and the diastolic heart failure. They are both equally common, and equally deadly. The systolic heart failure is easy to diagnose, as the CXR and echocardiographic changes are clear cut. As for diastolic heart failure ( usually accompanying hypertension ), it is harder to be definite. The CXR picture, maybe indistinguishable from systolic heart failure, and the echo findings of normal LV systolic function is so non-diagnostic. Mitral echogram of the E/A wave is so full of false positives and the LV wall thickness does have such a wide spectrum, especially in the elderly, that diagnosis requires much clinical skill.
Anyway, Sanofi-Aventis, the maker of irbesartan ( their ARB ), undertook a study 6 years ago, to see if irbesartan will improve CVS outcome in patients with Heart Failure and preserved LV systolic function. They followed 4,000 plus patients for slightly more than 4 years. These were hypertensives with a mean age of 72 years. When the study started, about 25% of the patients were on ACE-I, or beta-blockers or aldactone. When the study ended, about 33% of patients had droped out, and in about 38% of patients, the attending physicians had used ( protocol allowed ) more ACE-I, Aldactone or beta-blockers. This point may have "damaged " the trial.
To cut a long story short, the trial findings were neutral. Irbesartan did not improve the cardiac mortality or morbidity of the patients after 4 years. These findings were announced at the just concluded Annual Scientific Meeting of the American Heart association in New Orleans, last week.
Of course the search begins now to find out why. Very few "pharmas " will allow a negative or neutral trial to be reported, and highlighted.
In fact, I have just returned from Beijing where Sanifi Aventis held a regional discussion on Heart Failure with preserved LV systolic function in general and i-PRESERVE in particular. Dr P Carson ( the PI of i-PRESERVE was there ).
A few lessons that I learn. Firstly, Sanofi Aventis was careful ( for the brand and image ) that they will be forthcoming and that they do not mind the study ( although neutral ) talked about. They did not sweep it under the carpet ( as some pharmas were doin recently ). This I respect. Secondly, it would appear that allowing 30% drop-outs ( I think that cannot be avoided ) or even worse, a 20% drop-in ( where ACE-I, BB and Aldactone were allowed to be increase ) may have largely blunted the good effects of Irbesartan. ACE-I, Beta-blockers and aldactone are all very powerful agents that also affect the RAAS and also improve CVS mortality and morbidity. Of course the third lesson that I learn, was that Irbesartan at 300 mg daily ( that was the max. dose of Irbesartan allowed in the study ) may not be adequate to improve sysptoms in heart failure with preserved LV systolic function. Put another way, Irbesartan at 300 mg daily, may be effective in controlling hypertension, but may ot be adequate to improve CCF symptoms, thereby necessitating the need to use more ACE-I, Aldactone or Beta-blockers.
Looks like Irbesartan, has joined Candesartan ( CHARM-PRESERVE ), and perindopril ( PEP-HF ), in showing no mortality benefits when use in patients with preserved LV systolic function.
At the end of the day, it is true that i-PRESERVE, may have done more for us to better understand the workings of the RAAS, in Heart Failure with preserved LV systolic functions. Perhaps, as we said in Beijing, Irbesartan is a very good agent to control hypetension, and in that sense, prevent the onset of heart failure with preserved LV systolic function. It may not be a very good agent to use to try and improve the prognosis of heart failure with preserved LV systolic function.
Kudos to you, Sanofi Aventis, for coming clean in telling us that your study was neutral, and allowing us to understand the whole disease process better, even though it must have cost you plenty.

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