Composite endpoints

Another way of avoiding adjustment is to combine the multiple measurements into a single composite variable. Examples would be disease-lfee survival in oncology, where the variable is the time to either disease recurrence or death, whichever occurs first, or a composite of death, non-fatal stroke, MI and heart failure, a binary outcome in a cardiovascular setting. This approach does not require adjustment of the significance level we are back to having a single primary endpoint. 

There are some additional requirements, however, when using composite variables and these relate to the individual components, which should all be supportive of a difference in a single direction. A large positive effect with one of the components could potentially be masking a negative effect in a different component and this would be unacceptable. One way of investigating this would be to consider treatment effects in terms of the components singly. Alternatively, clinically appropriate combinations can be considered. For example, with the binary outcome, death, non-fatal stroke, MI and heart failure, one approach could be to break down the binary outcome into three separate outcome variables at the first level  

Each of these variables should be showing an effect in a consistent direction. At the second level, death on its own should be looked at and an effect confirmed. Providing treatment effects are seen to be consistently in the positive direction, these do not necessarily need to be statistically significant, a claim can be made in relation to the composite. 

The occurrence of individual cardiovascular events of interest in cardiovascular safety outcome trials is often low. An extremely large number of participants are therefore needed to provide the statistical power necessary to identify a statistically significant difference between tfeatment groups in the rates of occurrence of a given event of interest. One way to increase the likelihood of finding a difference between the treatment groups if one truly exists is to use a composite endpoint. A commonly employed choice is the major adverse cardiovascular events (MACE) composite endpoint, comprising of nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death. An alternative is called MACE-plus. In this case, various other events such as unscheduled hospitalization for revascularization are included, each of which must also be specified in the study s statistical plan. 

This approach reduces the number of study participants necessary to achieve the required statistical power in two ways. If the three individual components of the MACE composite endpoint (or the higher number of individual components in a MACE-plus composite endpoint) were compared separately between treatment groups, the numbers of events in each case would be lower than the total number of composite endpoint events. Moreover, a statistical correction would need to be made to address the issue of multiplicity as more comparisons are made, the chances of finding a statistically significant difference that does not in fact exist, i.e., committing a type I error, increase (recall discussions in Chap. 4). To counter this possibility, the alpha level (typically 0.05 for a single comparison) used for each of the multiple comparisons must be lowered. 

Using a composite endpoint, therefore, helps reduce the number of statistical comparisons of primary interest. If a trial s investigators are intent upon exploring a large range of endpoints, all of the other endpoints should be declared as secondary endpoints. It is common for statistical comparisons to be made for these secondary endpoints, but the degree of confidence that can be put in any individual finding  

Chow S-C, Liu J-P (2004) Design and analysis of clinical trials concepts and methodologies. 

DiNicolantonio JJ, Lavie CJ, Fares H, Menezes AR, O Keefe JH (2013) Meta-analysis of carvedUol versus beta 1 selective beta-blockers (atenolol, bisopiolol, metoprolol, and nebivolol). Am J Cardiol 111 765-769 

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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. 

The CAPRIE trial found that compared to aspirin (325 mg daily), clopidogrel (75 mg daily) was associated with RRR of 8.7% p = 0.043) for the composite endpoint of ischemic stroke, Ml, or vascular death among 19,185 subjects with stroke, MI, or peripheral arterial disease, but no significant reduction in the composite endpoint in the subgroup with stroke (RRR 7.3%, p = 0.26). No comparison of clopidogrel with aspirin in the acute stroke period was performed. Furthermore, stroke as an endoint was not significantly reduced in the stroke patients entered in this trial (RRR 8.0%, p = NS). 

The combination of nitrates and hydralazine improves the composite endpoint of mortality, hospitalizations for HF, and quality of life in African Americans who receive standard therapy. A fixed-dose combination product is available that contains ISDN 20 mg and hydralazine 37.5 mg (BiDil). Practice guidelines recommend adding ISDN and hydralazine as part of standard therapy in African Americans with moderately severe to severe HF. The combination may also be reasonable for patients of other ethnicities with persistent symptoms despite optimized therapy with an ACE inhibitor (or ARB) and /Tblocker. The combination is also appropriate as first-line therapy in patients unable to tolerate ACE inhibitors or ARBs because of renal insufficiency, hyperkalemia, or possibly hypotension. 

We all realize that we need better disease-specific endpoints in very many diseases. There are tremendous opportunities to use imaging and certain biomarkers, if only they could be relied upon. Patient-centered outcome measures are also extremely important in most chronic and symptomatic diseases yet, they are not used as extensively as they need to be. Agreement on acceptable composite endpoints is needed in many diseases. 

In some circumstances it may be necessary to combine several events/endpoints to produce a combined or composite endpoint. The main purpose in doing this is to again avoid multiple testing and more will be said about this in Chapter 10. In addition, combining endpoints/events will increase the absolute numbers of events observed and this can increase sensitivity for the detection of treatment effects. 

This was an open-label, parallel group, randomised trial in patients with chronic HIV-1 infection reported by van Leth et al. (2004). The primary endpoint was treatment failure, a composite endpoint based on virology, disease progression or therapy change. Initially patients were randomised equally to one of the following three groups ... 

Table 3 summarizes the primary results of these trials. Overall the use of GPIIb/llla inhibitors was associated with a modest, but significant reduction in the primary endpoint in PRISM, PRISM-PLUS, and PURSUIT Treatment benefit was confined to early time points in PRISM (48 hours) and PRISM-PLUS (seven days), but not sustained at 30 days (17,18). In contrast, treatment with eptifibatide reduced the incidence of composite endpoint by 1.5% absolute risk difference (ARD) in PURSUIT which was observed within four days and maintained for 30 days without attenuation or amplification (19). 

From these lines of evidence, it is apparent that the most likely reason for variability between interventional and medical management trials appears to be related to the frequency of early revascularization (100% in the former vs, <20% in the latter) and the utilization of periprocedural biomarker elevation criterion for Ml. Thus, treatment benefit associated with GPIIb/llla inhibitor is observed very early and is primarily driven by reduction in postprocedural biomarker elevation, the least robust but the most prevalent component of the composite endpoint with little benefit on death or Q-wave Ml. 

The results for bivalirudin group alone was 10.1% for the composite endpoint, P< 0.0001, 7.8% for the ischemic endpoint, P = 0.32, and 3.0% for major bleeding, P < 0.001 (all P-values for superiority). All causes of major bleeding were numerically lower with bivalirudin, except for intracranial hemorrhage, 0.07% versus 0.07%. Notably transfusions were less frequent with bivalirudin 2.7% heparin + GP llb/llla versus 1.6%, P< 0.001. Thus, the simpler regimen of bivalirudin alone resulted in significantly greater net clinical benefit (34). 

The FLORIDA study recruited 540 patients with Ml and a total cholesterol level of <6,5 mmol/L and randomized them to either fluvastatin 80 mg daily or placebo at a median time of eight days after symptom onset (22). The primary composite endpoint of the study was ischemia on ambulatory electrocardiogram monitoring or a major clinical event defined as death,... 

Based on these results treatment with an ACE inhibitor was recommended for patients with CAD and/or diabetes in addition to those indicated by the SAVE and SOLVD trials. The EUROPA trial (84) confirmed the HOPE results by demonstrating that ACE inhibitors were of benefit in the treatment of stable, low-risk patients with CAD as well. A 2% absolute risk reduction in the composite endpoint of cardiovascular mortality, nonfatal MI, and cardiac arrest was achieved using perindopril over a mean of 4.2 years. Patients with clinical heart failure were excluded and ejection fraction was not assessed. 

Other new echocardiographic methods have been employed in evaluation of PAH. One of them is strain imaging, which measures deformation over time it has been used in concert with TAPSE and RV Tei index (isovolumic contraction time and relaxation time/ejec-tion time [TVt - RVt]/RVt), and has been shown to be reduced in patients with acute pulmonary embolus and improved after stabilization (37). Using parameters of the eccentricity index, which highlight RV/LV interdependence, it was shown that an eccentricity index less than median was associated with improved survival and freedom from a composite endpoint (38). Lastly, the newer technique of vector velocity imaging applied to the right ventricle is promising as a quantitative assessment of RV function and reserve. 

In a recent meta-analysis of the six randomized trials, patient transfer for primary PCI was associated with a 42% reduction in the composite endpoint (death/reinfarction/stroke), compared with a strategy of on-site thrombolysis (Fig. 4.10) (95). This was driven mainly by a reduction in the incidence of reinfarction (68% reduction) and stroke (56% reduction), but there was also a trend toward improved survival with PCI. Overall, these findings strongly support community wide adoption of a transfer strategy for mechanical reperfusion, as long as patient transfer can be accomplished within time intervals similar to those described in the randomized trials. The challenge now is to overcome logistical obstacles and replicate these impressive results in clinical practice. 

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