Prevention trials

Ticlopidine inhibits the P2Yj2 platelet ADP receptor, thus inhibiting ADP-dependent activation of the GP Ilb/IIIa receptor. It has a slow onset of action and takes 3-7 days to reach its maximal antiplatelet effect. It is inactive in vitro and must undergo activation by the hepatic cytochrome p450 enzyme system. Secondary prevention trials have found that ticlopidine-treated patients have an estimated RRR of 33% for the composite endpoint of stroke, myocardial infarction, or vascular death after ischemic stroke. Significant adverse effects include bone marrow depression, rash, diarrhea, and thrombotic thrombocytopenic purpura. No clinical trials have studied ticlopidine for the treatment of stroke in the acute phase. 

Lacunar stroke is characterized by occlusion of a small penetrating artery creating a small deep infarct. Lacunar strokes have the lowest early recurrence risk and best survival rates, but may still cause significant functional morbidity. Although subgroup analyses are available from secondary prevention trials in lacunar stroke, few clinical trial data are available regarding nonthrombolytic antithrombotic therapy for lacunar stroke in the acute setting. 

Five randomized primary and secondary prevention trials " have demonstrated the efficacy and safety of warfarin in preventing AF-related stroke. Pooled data from these trials demonstrated a 68% reduction in ischemic stroke (95% Cl 50-79) and an intracerebral hemorrhage rate of <1% per year. The data for aspirin suggested that it had a lesser effect, with a 36% risk reduction (95% Cl 4—57). 

Primary prevention trial (Alpha-Tocopherol, 20 mg/day, 5 to 8 yr P-Carotene Lung cancer -t 35... 

Primary prevention trial (Physicians Health 20 mg/alternate days, 12 yr P-Carotene Lung cancer risk 0 37... 

Study) Primary prevention trial 6 mg/day beta-carotene, 7.5 years, P-Carotene Total cancer risk 15... 

Primary prevention trial (Beta Carotene and Retinol Efficacy Trial)... 

Primary prevention trial (a-Tocopherol, 5-Carotene Cancer Prevention Study)... 

However, intervention trials investigating the effects of P-carotene and lycopene supplementation on CVD have not reported convincing results (Table 3.1.3). Among the seven studies reviewed herein, four primary prevention trials, namely the Multicenter Skin Cancer Prevention Study, the Beta Carotene and Retinol Efficacy Trial, the ATBC cancer prevention study, " and the Physicians Health Study have shown no association between a supplementation of P-carotene and risk of death from CVD or fatal and non-fatal MI. 

Recent findings from the ATBC stndy even showed that P-carotene snpple-mentation increased the post-trial risk of a hrst-ever non-fatal MI. Two secondary prevention trials, the Heart Protection Stndy and the ATBC presented similar resnlts. The former showed no association between P-carotene and fatal or non-fatal vascular events and the latter reported signihcantly increased risks of fatal coronary events in the P-carotene-snpplemented gronp. Resnlts of clinical trials focused on the effects of carotenoids on CVD biomarkers are controversial. Although carotenoid supplementation increased sernm levels,only lycopene was shown to be inversely associated with lipid, protein, DNA and LDL oxidation, and plasma cholesterol levels. - - ... 

Early detection of ischemic stroke can be done with the use of transcranial Doppler ultrasonography. In the Stroke Prevention Trial in Sickle Cell Anemia (STOP) study, screening with this method followed by transfusion significantly reduced the incidence of stroke.29 Screening is recommended in all patients over 2 years of age. 

STOP Stroke Prevention Trial in Sickle Cell... 

A second problem with relapse-prevention trials is related to research suggesting that the use of antidepressants might make people more vulnerable to relapse. Patients who are being treated... 

These continuation trials tell a very different story from that told by relapse-prevention trials. They show that there is little difference between antidepressant and placebo even when the clinical trial is extended over a longer period of time. Across the eight continuation trials that have been published, 79 per cent of patients on placebo and 93 per cent of patients on active medication remained well throughout the treatment period. In these long-term studies, placebo treatment was 95 per cent as effective as drug treatment. The authors of a meta-analysis of these trials concluded that the widely held - and probably erroneous - belief that the placebo response in depression is short-lived appears to be based largely on intuition and perhaps wishful thinking .17... 

In the Breast Cancer Prevention Trial (Fisher et al. 1998) a clinical survey aimed at determining the potential of tamoxifen for breast cancer prevention in women at increased risk, 13,338 pre- or postmenopausal women were monitored over 5 years. After randomization, women in the treatment group (n = 6681) were given a 20-mg daily dose of tamoxifen, while the remaining (n = 6707) received a placebo. Although the overall rate of fractures was about the same in both groups, tamoxifen-treated women sustained fewer hip, spine, and Colles fractures. Nevertheless, relevant data may have been biased, since in this trial there was an indiscriminate inclusion of pre- and postmenopausal women and no spinal radiographs were carried out. 

The effects of tamoxifen in women with and without CHD have been analyzed in the National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial (BCPT). This randomized, placebo-controlled study included 13,388 women at increased risk for breast cancer. The conclusions of the trial are somewhat limited by the fact that it was designed to investigate the effect of tamoxifen as a chemopreventive for breast cancer, and not its effect on CVD risk. There was no indication that tamoxifen would modify the risk of CHD in women with or without heart disease (Reis et al. 2001). 

The most relevant study is the Breast Cancer Prevention Trial (BCPT, NSABP-P1) (Fisher et al. 1998). Initiated in the USA by the National Surgical Adjuvant Breast and Bowel Project, this study recruited 13,388 women considered at high risk for breast cancer based on Gail s probability algorithm (Gail et al. 1989). 

A recent review by Cuzick et al. has pooled the information generated by the four randomized prevention trials mentioned above (Cuzick et al. 2003). The observed reduction in breast cancer incidence was 38%, in good agreement with what was expected from the individual trials. When analyzing according to ER status, there was no reduction in the incidence of ER(-) tumors, and a reduction of 48% was observed in the incidence of ER(+) cancers. These figures clearly confirm that tamoxifen can reduce the risk of ER(+) breast cancer. 

Cuzick J, Powles T, Veronesi U et al. (2003) Overview of the main outcomes in breast-cancer prevention trials. Lancet 361(9354) 296-300... 

Decensi A, Maisonneuve P, Rotmenz N et al. (2005) Effect of Tamoxifen on venous thromboembolic events in a breast cancer prevention trial. Circulation 111 650-656... 

IBIS (2002) First results from the international Breast Cancer Intervention Study (IBIS-I) a randomised prevention trial. Lancet 360 817-824... 

Kedar RP, Bourne TH, Powles TJ, Collins WP, Ashley SE, Cosgrove DO, et al. (1994) Effects of tamoxifen on uterus and ovaries of postmenopausal women in a randomised breast cancer prevention trial. Lancet 343 1318-1321... 

From a clinical perspective, tamoxifen is still the first and only SERM worth mentioning from the first- and second-generation compounds. The pharmacology of tamoxifen has been reviewed extensively [142]. The NSABP-11 adjuvant trial and the Breast Cancer Prevention Trial (BCPT-1) are some of the milestones in the history of tamoxifen [141]. 

A review of these three trials concluded that, compared to antiarrhythmic therapy, ICD implantation for secondary prevention results in significant reductions in all-cause mortality (RR 0.76) and SCD (RR 0.50) [30]. A meta-analysis of secondary prevention trials found an absolute reduction in... 

Since survival rates for out-of-hospital cardiac arrest are quite low, ranging from 2 to 25% in the United States [32], secondary prevention strategies only address a small minority of ischemic cardiomyopathy patients at risk for SCD. A more substantial reduction in SCD will result from primary prevention of SCD with ICD implantation. Evidence for this strategy comes from several recent trials. The findings of primary prevention trials for SCD in ischemic cardiomyopathy are summarized in Table 3.1. 

Table 3.1 Summary of ICD primary prevention trials in ischemic cardiomyopathy ...

Survival curves in MADIT II did not separate until 9 months after enrollment, raising the question of when an ICD should be implanted after MI or revascularization. Two notable negative primary prevention trials may answer this question. The Coronary Artery Bypass Graft Patch (CABG-Patch) Trial evaluated whether primary prevention with ICD at the time of surgical revascularization in patients with EF < 35% and a positive SAECG would reduce total mortality [33]. At 32 months follow-up, no difference was found, suggesting that there is no additional benefit to ICD therapy at the time of revascularization. 

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