Negative Results Of Clinical Trials Research Articles

Negative Clinical Trial Results Less Likely to Be Published; Pfizer Said to Have Hidden Negative Trial Results

Negative Clinical Trial Results Less Likely to Be Published; Pfizer Said to Have Hidden Negative Trial Results

Hyperhomocystcinemia as a cardiovascular risk factor. Current concepts

Resume Hyperhomocysteinemia is hypothesized to be a cardiovascular risk factor. Severe hyperhomocysteinemia due to rare genetic impairments of homocysteine metabolism predisposes to atherothrombosis. Even partial correction of homocysteine levels in patients with severe hyperhomocysteinemia leads to significant reduction in cardiovascular risk. Moderate hyperhomocysteinemia is common in the general population and is associated with the increased risk of cardiovascular disease. Moderate hyperhomocysteinemia leads to endothelial dysfunction, increased susceptibility to thrombosis and accelerated progression of atherosclerosis in animal models. Extensive epidemiological and experimental evidence lead to the hypothesis that correction of moderate hyperhomocysteinemia may significantly lower cardiovascular risk. Paradoxically, several large clinical trials failed to demonstrate any benefit from lowering of homocysteine levels in moderate hyperhomocysteinemia. This article discusses the current understanding of hyperhomocysteinemia as a cardiovascular risk factor in light of the negative results of clinical trials of homocysteine lowering therapy in moderate hyperhomocysteinemia.

Effects of Transdermal Estrogen Replacement Therapy on Cardiovascular Risk Factors

The prevalence of hypertension and cardiovascular disease increases dramatically after menopause in women, implicating estrogen as having a protective role in the cardiovascular system. However, recent large clinical trials have failed to show cardiovascular benefit, and have even demonstrated possible harmful effects, of opposed and unopposed estrogen in postmenopausal women. While these findings have led to a revision of guidelines such that they discourage the use of estrogen for primary or secondary prevention of heart disease in postmenopausal women, many investigators have attributed the negative results in clinical trials to several flaws in study design, including the older age of study participants and the initiation of estrogen late after menopause.Because almost all clinical trials use oral estrogen as the primary form of hormone supplementation, another question that has arisen is the importance of the route of estrogen administration with regards to the cardiovascular outcomes. During oral estrogen administration, the concentration of estradiol in the liver sinusoids is four to five times higher than that in the systemic circulation. This supraphysiologic concentration of estrogen in the liver can modulate the expression of many hepatic-derived proteins, which are not observed in premenopausal women. In contrast, transdermal estrogen delivers the hormone directly into the systemic circulation and, thus, avoids the first-pass hepatic effect.Although oral estrogen exerts a more favorable influence than transdermal estrogen on traditional cardiovascular risk factors such as high- and low-density lipoprotein-cholesterol levels, recent studies have indicated that oral estrogen adversely influences many emerging risk factors in ways that are not seen with transdermal estrogen. Oral estrogen significantly increases levels of acute-phase proteins such as C-reactive protein and serum amyloid A; procoagulant factors such as prothrombin fragments 1+2; and several key enzymes involved in plaque disruption, while transdermal estrogen does not have these adverse effects.Whether the advantages of transdermal estrogen with regards to these risk factors will translate into improved clinical outcomes remains to be determined. Two ongoing clinical trials, KEEPS (Kronos Early Estrogen Prevention Study) and ELITE (Early versus Late Intervention Trial with Estradiol) are likely to provide invaluable information regarding the role of oral versus transdermal estrogen in younger postmenopausal women.

Inflammation and coagulation: implications for the septic patient.

Sepsis with acute organ dysfunction (severe sepsis) is common, frequently fatal, and associated with a significant national health/economic burden. In addition to standard care, investigators have focused on interrupting the inflammatory and anti-inflammatory cascade associated with this disease. Unfortunately, despite promising preclinical results, interventions directed at the inflammatory elements have not reduced the morbidity and mortality associated with this disease. Inflammation and coagulation are tightly linked. In fact, sepsis-associated coagulopathy is almost universal in patients with severe sepsis. Preclinical observations indicate that antithrombotic-targeted therapy has the potential to reduce morbidity and mortality in patients with this disease. Treatment with recombinant human activated protein C (drotrecogin alpha [activated]) was the first antithrombotic-targeted therapy to significantly reduce 28-day all-cause mortality in patients with severe sepsis. The pathophysiological and clinical significance of this evidence and the relationship of coagulation to inflammation are discussed, as are positive and negative results of clinical trials of antithrombotic therapy.

Antihypertensive calcium channel blockers may promote human cancer cell growth

It has been suggested that calcium ion (Ca2+) channel blocking drugs (CCB), commonly employed as antihypertensive agents, may promote growth of pre-existing cancer cells by inhibition of apoptosis. So far, however, there are no experimental data to support this notion, and results from clinical trials and epidemiological studies have been negative or ambiguous, respectively. Therefore, we examined if vascular type (L-type) Ca2+ channels are expressed in human colon cancer cells and if L-type Ca2+ channel activators (CCA) and blockers (CCB) influence Ca2+ influx and subsequent apoptosis in such cells. Both primary (collected at operation) and commercially available human colon cancer cell lines were used. The cells were incubated with three different CCB (verapamil, diltiazem or nifedipine) and one CCA (BayK 8644) at clinically relevant concentrations. RNA was determined by reverse-transcription polymerase chain reaction (RT-PCR SuperScript one-Step). Intracellular Ca2+ levels were measured by fluorometry (Fluo-4-AM). Apoptosis was quantified by flow cytometry (Annexin V binding). Cells from both lines expressed vascular (L-type) Ca2+ channel mRNA but neither N- nor P-type channel mRNA. The L-type Ca2+ channels were composed of a1D and b3- subunits. The selective L-type CCA BayK 8644 markedly increased Ca2+ influx and apoptosis in the cells, and CCB pretreatment abolished BayK 8644-induced Ca2+ influx and apoptosis. Accordingly, while there is no evidence that CCB transformation of normal cells to cancer cells, these drugs may promote growth: of pre-existing cancer cells in humans. As this would become clinically relevant only in subjects who already harbor a critical mass of cancer cells, the negative results in clinical trials and the conflicting results of epidemiological studies are not surprising. Until studies have been conducted in appropriate patient groups to substantiate or refute the notion that CCB treatment poses a real cancer threat, it seems prudent to minimize the use of CCB in hypertensive patients.