of lesions per patient seems to us also important for risk stratifica- tion, because each coronary lesion is a risk for myocardial infarction. A patient with 5 new stenoses is cer- tainly at a higher risk than a patient with only 1.

Hence, if one is performing a meta-analysis, all the facts should be weighted very carefully. Finally, if the possibility of an adverse effect of a drug on myocardial infarction is analyzed, one should primarily deal with cardiac and not total mor- tality.

Paul R. Lichtkn, MD Hannover, Germany

8 July 1991

1. Yusuf S, Held P, Furberg CD. Update of effects of calcium antagonists in myo- cardial infarction or angina in light of the second Danish Verapamil Infarction Trial (DAVIT-II) and other recent studies. Am J Cardiol 1991;67:1295-1297. 2. Lichtlen PR, Hugenholtz PG, Rafflen- bet11 W, Hecker H, Jost ST, Deckers JW, on behalf of the INTACT group investi- gators. Retardation of angiographic pro- gression of coronary artery disease by nifedipine; results of the International Nifedipine Trial on Antiatherosclerotic Therapy (INTACT). Lancer 1990;335: 1109-1113. 3. Lichtlen PR, on behalf of the INTACT study group. Reply to the letter of Drs. M.R. Goldstein and F.W.A. Verheugt as well as a letter. from unknown authors to the article on INTACT, Lancet 1990; 335:1109-1113. Lancet 1990;336:172- 174. 4. Lichtlen PR, Hugenholtz PG, Rafflen- beul W, Hecker H, Jost ST, Nikutta P, Deckers JW, on behalf of the INTACT group investigators. Retardation of coro- nary artery disease in humans by the cal- cium-channel blocker nifedipine: results of the INTACT study (International Ni- fedipine Trial on Antiatherosclerotic Therapy). Cardiovascular Drugs and Therapy 1990;4(suppl 5):1047-1068.

REPLY: We thank Professor Licht- len for his comments regarding our article. He raises 2 issues: The first issue relates to our use of all-cause instead of cardiac mortality from the INTACT study.’ The large ma- jority of overviews of randomized clinical trials in cardiovascular dis- ease have focused on all-cause mor- tality, including our original arti- cle* and the recent update.3 All- cause mortality has the distinct advantage of being based on a sim-

ple count without any element of judgment and, thus, essentially be- ing free of bias. It is also available from all trials. Since 80 to 90% of deaths in cardiovascular trials are cardiac, and there are no data to suggest that nifedipine increases the risk of noncardiac deaths, the difference between an overview re- porting on all-cause or cardiac mor- tality is small. We believe that this is worth the price of obtaining com- plete and bias-free data, especially in secondary prevention trials.

In small trials with few deaths, such as INTACT, the play of chance may give the appearance of a distinction between various modes of deaths. The strength of our overview is the inclusion of all known trials of calcium antagonists rather than focusing on a specific trial. The overall data suggest that mortality is increased with the use of dihydropyridine calcium antago- nists. However, there may be some uncertainty concerning the magni- tude of the adverse effect.

The second issue raised by Licht- len regards the presentation of an- giographic data from his trial. It appears that the primary goal of his trial was to assess angiographic progression overall. There is no dif- ference between the active and con- trol groups on this end point. The claim of an effect on prevention of new lesions is data-derived and, moreover, utilizes inappropriate statistical methods. Randomization in this trial is by patient (not by lesion), and therefore, the unit of analysis has to be the individual pa- tient.2 From a physiologic point, the rates of lesion changes in different parts of a coronary tree within an individual patient are likely to be correlated. Moreover, the entire coronary tree within an individual is subjected to the same interven- tion.

Therefore, the analysis of the de- velopment of new lesions has to take the unit of randomization (which is the individual patient and not each lesion) into account. In the primary paper,’ the only analysis that uti- lizes such an approach is the com- parison of the number of patients in each group who develop new lesions (70 of 173 in the active vs 85 of 175 in the control). This is not statisti-

cally significant. Furthermore, in 18% of patients, follow-up angio- grams were not available. The po- tential influence of these missing data on the analysis requires clarifi- cation.

The only analysis that includes all randomized patients and reaches statistical significance in INTACT is the adverse effect of nifedipine on total mortality. Whereas the ap- parent excess may be exaggerated by the play of chance in this trial, the adverse trend is consistent with data from other related trials of dihydropyridines calcium antago- nists. Therefore, the totality of evi- dence indicates that on balance these agents are likely to be more harmful than beneficial to patients with ischemic heart disease. There are no data indicating benefit to clinical end points in such patients.

SaWm Yusuf, wu8, wee, DpN Bethesda, Maryland

Peter Held, PhD Goteborg. Sweden Curl Furberg, MD

Winston Salem, North Carolina 20 September 199 1

1. Lichtlen RP, Hugenhoitz PG, Rafflen- beul W, Hecker H, Jost S, Deckers JW. Retardation of angiographic progression of coronary artery disease by nifedipine: results of the International Nifedipine Trial on Antiatherosclerotic Thera- py (INTACT). Lancer 1990;335:1109- 1113. 2. Held PH, Yusuf S, Furberg CD. Calci- um channel blockers in acute myocardial infarction and unstable angina: an over- view. Br Med J 1989;299:1187-1192. 3. Yusuf S, Held P, Furberg CD. Update of effects of calcium antagonists in myo- cardial infarction or angina in light of the second Danish Verapamil Infarction Trial (DAVIT-II) and other recent studies. Am J Cardiol 1991;67:1295-1297. 4. Yusuf S, Garg R. Randomized trials to assess the long term effects of therapies on angiographic endpoints. Chest 1991;99: 1243-1247.

Atrial Natriuretic Factor and Transfnural Pressures

Serra et al1 contribute important insights into the physiology of atria1 natriuretic factor (ANF) release by demonstrating attenuation in ANF production in patients with right ventricular (RV) infarction compli- cating inferior wall left ventricular infarction. They suggest plausible mechanisms, including RV necrosis

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