Saphenous vein graft failure as a Surrogate Endpoint in Clinical Trials

Overview
One issue that arises is the suitability of SVG patency, and SVG narrowing as a surrogate endpoint for clinical events. A surrogate marker (or surrogate end point) is term used in medical research for a change to the human body that is believe to be necessary to an eventual outcome or end point. In clinical trials, a surrogate endpoint is a measure of the effect (often what is known as a biomarker like cholesterol) of a certain treatment that is substituted in the  evaluation of a new drug or device in place of a "hard endpoint" like  death or heart attack. The National Institutes of Health (USA) defines surrogate endpoints as: "A biomarker intended to substitute for a clinical endpoint". The use of a surrogate endpoint can lead to more rapid and efficient completion of clinical trials, but the use of a surrogate endpoint has been criticized as reductions of a substitute maker are not always predictive of improvements in clinical outcomes. The classic example of a failed surrogate marker is the use of PVC suppression as a substitute  marker of anti-arrhythmia effectiveness. Class III anti-arrhythmias reduced PVCs or extra heart beats, but were associated with a higher risk of death in the Cardiac Arrhythmia Suppression Trial (CAST). Surrogate markers may be used when it is unethical to look for the end point (e.g., death) in the experiment, or when the number of end point events is very small, thus making it impractical to conduct an experiment to look for the end point. The measurement of surrogate markers provides a way to test the effectiveness of a treatment for a fatal disease without having to wait for a statistically significant number of deaths to occur. The FDA will often accept evidence from clinical trials that show a benefit with respect to surrogate markers instead of hard clinical end points.

The Advantages of a Surrogate Endpoint
The assessment of "hard" primary clinical endpoints (such as death and  heart attack) often requires large long-term clinical trials which can  be quite expensive. The use of surrogate endpoints can allow trials to evaluate the efficacy of a new drug or device more rapidly, more  efficiently and more inexpensively.

The Disadvantages of Surrogate Endpoints
There are several potential disadvantages of a surrogate endpoint.

1. The surrogate endpoint may intuitively be hypothesized to be related to a "hard endpoint" such as death or heart attack, but may not be. 2. While a surrogate endpoint may be related to a "hard endpoint" such as death or heart attack, it is not clear that a reduction in the surrogate endpoint will lead to an improvement in the "hard endpoint" in death or heart attack. Anti-diabetic agents have been shown to reduce long term glucose (Hemoglobin A1c or HbA1C). It was hypothesized that more intense glucose control (a reduction in HbA1C) would be associated with a lower rate of  death and heart attack. However, despite lowering of HbA1C, rosiglitazone or Avandia was not associated with a reduction in death and MI, but with an increase in the RECORD trial.

In another example, class III antiarrhythmic agents were associated with suppression of premature ventricular contractions or PVCs, but were associated with a higher rate of death.

3. While a surrogate endpoint may be related to a "hard endpoint, it may  be an acausal association (the surrogate may not lie in the causal  pathway to the "hard endpoint" and changing the surrogate endpoint may  not change the "hard endpoint".)

4. The agent may reduce the surrogate endpoint, but due to off target toxicity, may increase the  risk of "hard endpoints" such as death or MI. Lower HDL is associated with a higher risk of adverse cardiac outcomes, Torcetrapib raises HDL and should therefore improve clinical outcomes, however, Torcetrapib administration was found to be associated with a higher rate of adverse  clinical outcomes. It was felt that the potential benefit of Torcetrapib was reversed due to off target toxicity of a slight increase in blood pressure associated with Torcetrapib administration.

5. The relationship between the surrogate endpoint and the "hard endpoint"  may be non-linear or may be a threshold effect. For example, in antiplatelet agent studies, it is unclear if ever greater levels of  inhibition of platelet aggregation are associated with ever greater  reductions in adverse outcomes, or if one must achieve just a certain  "threshold" level of inhibition to improve outcomes.

There have  been a number of instances when studies using surrogate markers  have  been used to show benefit from a particular treatment, but later, a   repeat study looking at endpoints has not shown a benefit, or even a   harm.

Examples of Surrogate Endpoints
Examples of surrogate markers include:
 * Total cholesterol
 * High density lipoprotein (HDL)
 * Low density lipoprotein (LDL)
 * c reactive protein (cRP)
 * Platelet inhibition by light transmittance aggregometry
 * Coronary blood flow
 * Minimum diameter or an artery and restenosis
 * Fragmented blood cells are a surrogate marker for organ failure or stroke in TTP
 * The S-phase duration, may be used as a surrogate marker for breast cancer occurrence
 * CD4 count is a surrogate marker for death from HIV infection

Evaluation of a Surrogate Endpoint
A surrogate may be suitable as a surrogate endpoint if the following three criteria are satisfied:


 * 1) The drug or device improves the surrogate
 * 2) Improvement in the surrogate is related to an improvement in a hard clinical endpoint
 * 3) The same drug or device improves the hard clinical endpoint

In order for a surrogate to be validated, there must be at least one large  clinical trial that satisfies these criteria. After this, other studies could rely upon the surrogate if it has been validated in a large  study.

Caveats in the use of SVG Failure as a Surrogate Endpoint
There are multiple studies demonstrating that SVG closure or failure is associated with clinical events. The association of SVG failure or narrowing with clinical events is complex and should be interpreted in light of the following nuances:


 * 1) Often a composite endpoint of death, MI and revascularization is reported. One must be careful to deconstruct this composite endpoint to look at the association between SVG failure and each of these endpoints separately.
 * 2) It can be useful to distinguish between an MI that precedes and MI that follows revascularization to treat SVG failure. Understanding the timing of the myonecrosis allows one to undersantd the mechanism that caused the MI. An MI that precedes revascularization may be temporally attributable to the SVG failure itself, rather than the revascularization procedure to treat the SVG failure. A limitation to this assertion is that the release of markers of myonecrosis may be delayed, and a late rise in a cardiac biomarker may not be solely due to the revascularization, but it may also be related to the original occlusion of the SVG.  After PCI for early SVG failure, 20.6% sustain an MI, and 30.6% of PCIs for late SVG failure are associated with MI (creatine kinase-myocardial band (CK-MB) greater than twice normal) .  However, whether the MI preceded the intervention to treat SVG failure, or followed the intervention to treat SVG failure, SVG failure can reasonably be deemed to be the proximate cause of the event.
 * 3) One must be careful to distinguish between a) immediate peri-operative MIs during the index hospitalization, b) early MIs between the index hospitalization and a year, and c) late MIs (after a year).  If one is evaluating a therapy targeted at reducing late atherothrombosis or drugs that reduce intimal hyperplasia, then events between b and c are most relevant. If one is investigating a therapy targeting thrombotic occlusion, then all periods (a,b, and c) are relevant.
 * 4) In observational studies, those patients who are alive to undergo repeat angiography are obviously included in the analyses, and those patients who died prior to angiography may not be included in the observational analysis (i.e. there may not be imputation of an SVG failure to those patients who died). This results in underestimation of the association between SVG failure and mortality. For example, a report from the Duke Databank included those patients who survived to undergo subsequent cardiac catheterization, and excluded those patients who died by did not undergo cardiac catheterization.
 * 5) The SVG may close and the native artery may remain open minimizing the  symptoms associated with SVG failure.  SVG failure may therefore by  clinically "silent" or may not be closely associated with "hard  endpoints" such as myocardial infarction(MI).
 * 6) Despite the native artery remaining open after SVG failure, it should be  realized that placement of an SVG is associated with more rapid disease  progression in the grafted native coronary artery.  SVG placement  therefore exposes the patient to a risk of more rapid native disease  progression. There is a 4 to 6 fold increase in the risk of proximal  native vessel occlusion following the placement of an SVG, while there  is limited impact upon disease progression downstream from the SVG     . While long-term studies demonstrate that as many as 22/23 grafted  vessels occlude proximal to the SVG insertion site, the patency beyond  the SVG insertion remains better (only 8 of 39 segments failed) .  Progression of native disease is more rapid in segments bypassed by and  SVG than those bypassed by an arterial conduit (p = 0.001, odds ratio =  2.03) .  In summary, if the SVG fails, the patient most often is left with  greater progression of the underlying native vessel disease than they  would have had had they not had an SVG placed. It is difficult to  ascertain the impact of native vessel disease acceleration given the  limited duration of follow-up in trials of SVGs. The impact of disease  progression may not be apparent for many years and may be underestimated  in current trials and analyses.
 * 7) As a nuance of the above, the impact of SVG failure may depend in part upon when it occurs.
 * 8) SVG failure not only leads to a potential reduction in antegrade blood flow  to the bypassed segment as a result of vessel closure, there is also the potential for embolizaiton from a large occluded conduit into the downstream native circulation.  SVGs do not have sidebranches and there  is therefore no capacity for alternate run off when occlusion occurs. As  a result, SVGs often occlude back to the origin of the SVG.  Furthermore, the diameter of SVG often exceeds that of native arteries.  As a result of the fact that the SVG occludes back to the ostium and is  of a larger volume than a native coronary artery, there is a much larger  embolic burden associated with a SVG.
 * 9) Consistent with the embolic hazard cited above, is the fact that dilation of an  SVG failure does not lead to improved clinical outcomes. The fact that  opening a closed SVG does not lead to improved outcomes may lead to  inappropriate confusion surrounding SVG failure as a relevant clinical  outcome.  While it may be intuitive that opening an occluded or failed  SVG would lead to improved outcomes (consistent with SVG failure being a  surrogate), opening the occluded SVG may instead lead to embolizaiton  of a large amount of the thrombotic material downstream.  Preventing  SVG occlusion may be related to improved outcomes, but treating SVG  occlusion after it occurs may not be related to improved outcomes.  The failure of reopening an occluded SVG to improve outcomes should not  detract from the importance and relevance of preventing SVG occlusion  in the first place as a valid surrogate endpoint.
 * 10) The patient is the unit of randomization, but failure of an SVG is the unit most closely related to clinical events.
 * 11) The impact of SVG failure must be interpreted in the context of the presence and patency of arterial conduits. The impact of SVG failure that includes failure of an SVG to the left anterior descending may be quite different than failure of an SVG to the RCA in the presence of a patent left internal mammary artery.
 * 12) The impact of SVG failure must be interpreted in the context of the patency and disease status of the native vessel.
 * 13) The impact of SVG failure must be interpreted in the context of left ventricular function as well as associated co-morbidities (renal failure, diabetes and advanced age which are all associated with SVG failure).
 * 14) Is the timing of SVG failure relevant? If an anticoagulant (either antiplatelet or antithrombin) is undergoing evaluation of its efficacy in the prevention of  thrombotic graft closure, then it is irrelevant if this thrombotic  closure is early (in the immediate peri-operative period) or late.  It  could be hypothesized that the clinical benefit of the anticoagulant  agent would be operative during both the early and late follow-up  periods.
 * 15) Patients may not return for follow-up angiography and this may result in ascertainment bias.  Maybe the patient is feeling so well they don't feel compelled to  return for repeat angiography (you missed a positive treatment effect),  or maybe they are so sick they can't show up (you missed a negative  treatment effect).  If patients died, traditionally they are counted or  imputed as having SVG failure on both a per patient and a per SVG  conduit basis. The percent of patients who returned for follow-up  angiography was 80% in the PREVENT 4 study
 * 16) The patient may return for follow-up angiography, but one or more of the SVGs cannot be engaged and selectively injected.  As stated above, in the PREVENT 4 study, the use of saphenous vein  graft markers improved the odds of finding SVGs in particular occluded  SVGs .  However, the SVG stenosis 70% or greater at follow-up did not differ by use of markers (25.8% with marker vs 24.4% without marker, p = not significant). In other words, there does not seem to be ascertainment  bias whereby failure to find the SVG results in a different outcome (the  outcomes in patients with SVG markers with a greater degree of ascertainment of the endpoint were no different).
 * 17) There are both per patient and per SVG units of analysis. Analyses should be presented on both a per patient basis (the unit of randomization) and a per SVG basis (the unit that is associated with  clinical events).  Because the behavior of multiple SVGs may be  correlated, and this within patient correlation may reduce the estimate  of the variance in the population, an adjustment for the within patient correlation must be provided when presenting the results on a per SVG  basis .  The within patient conocrdance can be adjusted for using a General Linear Model of Intraclass Correlation (GLIMIC).

Association of SVG Failure with Clinical Events
There are multiple mechanisms whereby SVG patency is related to clinical outcomes:
 * 1) Closure of the conduit may reduce antegrade blood flow
 * 2) There  may be embolization into the native vessel from the thrombosed SVG   conduit, the diameter of which often exceeds the native coronary artery
 * 3) The SVG may have accelerate native vessel disease which predisposes the patient to adverse outcomes when the vessel occludes

Fitzgibbon and colleagues evaluated the clinical outcomes among 1,388 patients with 5,065 grafts over 25 years at a single center. SVG occlusion occurring 1 year after CABG was associated with reoperation and mortality.

In the PREVENT 4 study, the rate of death or MI outside the immediate perioperative period was 13.9% among patients with SVG failure and 0.9% among those without SVG failure. The rate of immediate perioperative MI among patients with SVG failure was 13.4 and 6.8% among those patients without SVG failure.

Association of SVG Failure after Stenting with Clinical Events
The impact of SVG failure on clinical outcomes after SVG stenting was demonstrated among 80 patients with 112 lesions in the SOS (Stenting Of Saphenous Vein Grafts) Trial. Compared with BMS, DES (specifically paclitaxel elution) was associated with a reduced risk of SVG failure. SVG failure after stenting was associated with an acute coronary syndrome in 10 of the 24 patients (42%). 7 of the 24 (29%) of patients presented with a non–ST-segment elevation acute myocardial infarction). Stable angina was present in 9 (37%) of SVG failure patients, and there were no symptoms in 5 (21%) SVG failure patients. The authors concluded that SVG failure after stenting presents as an acute myocardial infarction in 7/24 (30%) of cases.   It is quite clear that SVG failure in an SVG that has had a stent placed is associated with worse clinical outcomes, and by extension, it stands to reason that SVG failure may be associated with worse clinical outcomes as well.

Association of Primary PCI of Acutely Occluded SVGs with Adverse Events
In several studies, if an SVG is the culprit vessel in acute MI, mortality is quite high.

Indeed, some investigators have demonstrated that the mortality associated with SVG occlusion presenting as an MI and requiring intervention may be greater than that of native vessels. In the Mayo experience, a total of 1,072 patients with acute MI underwent primary PCI without prior lytics between 1991 and 1997. A total of 128 patients had previously undergone CABG and 944 had not undergone CABG. Of the patients who had previously undergone CABG, the primary PCI was performed in the native vessel in 65, and in the SVG itself in 63. In a multivariate model adjusting for co-morbidities, primary PCI of an SVG was independently associated with adverse cardiac events (death/MI/Repeat revascularization) (relative risk 1.48 [95% confidence interval 1.07-2.03], P =.02), but a history of prior CABG itself was not (relative risk 1.22 [95% confidence interval 0.96-1.56], P =.11).

In another study, patients with a thombosed SVG were at very high risk of subsequent events including mortality. The acute and long-term outcomes among 34 consecutive patients who underwent PCI of 36 acutely occluded SVGs between 2003 and 2009 at one institution were evaluated. Although PCI of the SVG was successful in 81% of the patients, 39% of these patients sustained stent thrombosis. After a mean follow-up of 2.3 ± 1.9 years, the mortality at 1 year was 8% and the mortality at 3 years was 42%. An acute coronary syndrome occurred in 15% of patients at 1 year and in 41% of patients at 3 years.