|
|
|
|
|
|
|
But clearly defined target levels do not exist and studies have not reported any difference in blood levels in patients who were protected by Holter analysis or at programmed electrical stimulation testing compared to those who were not protected. In the field of CHF, dose is also a difficult and vexing question. Digitalis is employed at the most minimum of doses to avoid toxicity, whether high doses would be more beneficial is currently unknown since the spector of toxicity is what we try to avoid against clinically. The ACE inhibitors are a major contribution to the field and a number of studies have shown that they reduce mortality in patients with severe and also moderate congestive heart failure. But what dose is the most effective? What should be the dose that is targeted clinically? These are unanswered questions despite the body of evidence attesting to the efficacy of ACE inhibitors in congestive heart failure. The ACE inhibitors lower blood pressure and a dose of ACE that lowers BP, but does not cause prohibitive side effects, is one that is selected often for testing in clinical trials. We must ask ourselves: what is the correlation of the effect of the ACE inhibitor on blood pressure and the outcome in heart failure patients? The answer to this important question is clearly unknown. A substudy of the NIH program in heart failure (SOLVD) study reported that patients with a greater inhibition of converting enzyme did better than those showing a lower inhibition (3). Perhaps dose should be established on the basis of ACE inhibition. Clearly there is considerable confusion in the field and the confusion probably diminishes the use of ACE inhibitors because this degree of uncertainty to physicians decreases their likelihood of employing the ACE and encourages them to use such low doses of ACE as to be homeopathic. |
|
|
|
|
|
|
|
|
Lipid therapy is another area where correlation of the dose has not been established for clinical effect. The surrogate of reduction in cholesterol is the target we have chosen for clinical therapy. However, in clinical studies a fixed dose was employed, cholesterol was reduced but was not necessarily pushed to a target cholesterol level. We see benefit in secondary prevention in some trials. This is very different than pushing to a target cholesterol and seeing what would happen in terms of outcome. However, the target cholesterol must be considered suspect since we really have no definitive evidence that it is the cholesterol lowering to a target level that is causing benefit. Do we know that the cholesterol target is optimum or should cholesterol be lowered even further? The Simvastatin Trial showing a marked secondary prevention gain may not relate to cholesterol lowering per se, but to changes caused in the vascular biology-altering plaque rupture proclivity and platelet aggregation (4). The gain in luminal diameter has only been modest as demonstrated by quantitative angiography studies and, thus the small improvement documented in luminal diameter is unlikely to be the mechanism of the mortality benefit. What dose should therefore be employed in the future lipid trials is another conundrum in drug development. We have certain doses that work. We have certain targets |
|
|
|
|
|