Surrogate Endpoints In Trials Research Articles

Abstract 2964: On-treatment changes in circulating tumor DNA (ctDNA) level as an early predictor of clinical outcome in the LOTUS randomized phase 2 trial of 1st-line ipatasertib (IPAT) + paclitaxel (PAC) for metastatic triple-negative breast cancer (mTNBC)

Abstract Purpose: There is high interest in longitudinal analysis of plasma ctDNA as an early predictor of response and long-term outcomes. We report a retrospective longitudinal analysis of ctDNA in the double-blind placebo (PBO)-controlled randomized phase 2 LOTUS (NCT02162719) trial of the oral Akt inhibitor IPAT + PAC for mTNBC. Methods: Pre-treatment plasma samples were analyzed to identify and quantify genomic alterations in ctDNA using a hybrid-capture-based NGS assay that interrogates 62 genes (FoundationACT). A narrow ctDNA panel quantified the same mutations in on-treatment samples collected at 8 wks (d1, cycle 3). The ctDNA fraction (CTF) was defined as the highest mutant allele frequency in each sample. The ratio of CTF in on-treatment vs pre-treatment samples was compared with objective response (RECIST v1.1) and progression-free survival (PFS) in the experimental (IPAT + PAC) and control (PBO + PAC) arms. Results: Paired on-treatment samples were evaluable from 66 of 88 patients with evaluable pre-treatment samples. The most common reason for no on-treatment sample was disease progression (PD) before cycle 3. In 81 baseline samples, 149 mutations were identified. Calculated CTF ratios ranged from 0% (not detected in on-treatment sample) to 648% (increase in on-treatment sample). In both arms and the pooled population, a greater CTF decrease was associated with objective response and longer PFS (Table). Conclusions: On-treatment change in CTF shows a meaningful association with objective response and PFS in LOTUS. This effect was seen in the experimental and control arms, suggesting independence from the specific mechanism of therapy. Evaluation of samples from the time of PD is ongoing. Inclusion of additional timepoints will likely improve the predictive ability of CTF, possibly allowing its use as an early surrogate trial endpoint. IPAT + PAC (n=32)PBO + PAC (n=34)Pooled arms (n=66)Median CTF ratio, % (IQR)Confirmed complete/partial response(n=14)(n=14)(n=28)0.4 (0-14.3)0.2 (0-46.9)0.3 (0-17.8)Stable/progressive disease(n=18)(n=20)(n=38)8.2 (4.4-45.9)26.9 (8.4-91.4)20.7 (4.9-67.9)Median PFS, months (95% CI)CTF ratio ≤5%(n=15)(n=14)(n=29)7.2 (3.7-NE)6.3 (3.6-NE)7.2 (5.1-12.9)CTF ratio >5%(n=17)(n=20)(n=37)3.7 (3.5-5.3)3.7 (2.8-5.4)3.7 (3.6-5.0)PFS hazard ratio (95% CI)0.46 (0.19-1.09)0.43 (0.17-0.97)0.43 (0.23-0.78)CI = confidence interval; IQR = interquartile range; NE = not estimable. Citation Format: Matthew J. Wongchenko, Doron Lipson, Travis Clark, Mark Kennedy, Mandy Greene, Virginia Breese, Alyssa Tsiros, Sung-Bae Kim, Cristina Saura, Mafalda Oliveira, Jose Baselga, Amy V. Kapp, Wai Y. Chan, Stina M. Singel, Steven Gendreau, Rebecca Dent. On-treatment changes in circulating tumor DNA (ctDNA) level as an early predictor of clinical outcome in the LOTUS randomized phase 2 trial of 1st-line ipatasertib (IPAT) + paclitaxel (PAC) for metastatic triple-negative breast cancer (mTNBC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2964.

The Search for Surrogate Endpoints in Trials in Diffuse Large B-Cell Lymphoma: The Surrogate Endpoints for Aggressive Lymphoma Project.

This commentary describes the progress of the SEAL [Surrogate Endpoints for Aggressive Lymphoma] research group and invites collaboration in sharing data to continue building a large database of individual patient data from multiple clinical trials in DLBCL.

Nonpublication of trial results for new neurological drugs: A systematic review.

To evaluate nonpublication rates among trials of new successful and unsuccessful neurological drugs. "Licensed" drugs consisted of all novel agents receiving US Food and Drug Administration (FDA) licensure 2005-2012 inclusive in seven neurological disorders. "Stalled" drugs included all experimental agents tested in the same domains that had at least one completed phase III trial in the same time frame, but failed to receive FDA approval. Trials of these drugs were included in our sample if their primary outcome collection occurred before October 1, 2010. We determined the publication status of eligible trials using searches of clinicaltrials.gov, Google Scholar, PubMed, Embase, sponsor websites, and direct electronic query of trial contacts and sponsors. The primary outcome was time to journal publication (or results reporting in other media) after study completion. The adjusted hazard ratio for publication was 1.79 (95% confidence interval, 1.20-2.67) in favor of licensed drugs. Based on the criteria for nonpublication in this report, 14,092 and 33,882 volunteers participated in unpublished trials of licensed and stalled neurological drugs, respectively. Result data were not publicly available in any form for 10% (16 of 163) and 46% (94 of 203) of trials of licensed and stalled drugs, respectively. Results of trials for stalled drugs are heavily under-reported. This deprives research and care communities of evidence about pathophysiology, drug class effects, and the value of surrogate endpoints in trials. Ann Neurol 2017;81:782-789.

Two Decades of Cardiovascular Trials With Primary Surrogate Endpoints: 1990-2011.

BackgroundSurrogate endpoint trials test strategies more efficiently but are accompanied by uncertainty about the relationship between changes in surrogate markers and clinical outcomes.Methods and ResultsWe identified cardiovascular trials with primary surrogate endpoints published in the New England Journal of Medicine, Lancet, and JAMA: Journal of the American Medical Association from 1990 to 2011 and determined the trends in publication of surrogate endpoint trials and the success of the trials in meeting their primary endpoints. We tracked for publication of clinical outcome trials on the interventions tested in surrogate trials. We screened 3016 articles and identified 220 surrogate endpoint trials. From the total of 220 surrogate trials, 157 (71.4%) were positive for their primary endpoint. Only 59 (26.8%) surrogate trials had a subsequent clinical outcomes trial. Among these 59 trials, 24 outcomes trial results validated the positive surrogates, whereas 20 subsequent outcome trials were negative following positive results on a surrogate. We identified only 3 examples in which the surrogate trial was negative but a subsequent outcomes trial was conducted and showed benefit. Findings were consistent in a sample cohort of 383 screened articles inclusive of 37 surrogate endpoint trials from 6 other high‐impact journals.ConclusionsAlthough cardiovascular surrogate outcomes trials frequently show superiority of the tested intervention, they are infrequently followed by a prominent outcomes trial. When there was a high‐profile clinical outcomes study, nearly half of the positive surrogate trials were not validated. Cardiovascular surrogate outcome trials may be more appropriate for excluding benefit from the patient perspective than for identifying it.

Carotid Intima-Media Thickness as a Cardiovascular Risk Factor and Imaging Pathway of Atherosclerosis.

Assessment of carotid intima-media thickness (IMT) has emerged as a simple and noninvasive technique for measuring atherosclerotic burden. Although serum biomarkers have been linked to the risk of developing atherosclerosis, carotid IMT has the theoretical advantage of directly visualizing a final consequence of the disease itself, namely atherosclerosis in the vessel wall. The current widespread application of carotid IMT measurements has been based on the validity, standardization, and reproducibility of the measurement and the evidence that an increased carotid IMT can be regarded as an attractive biomarker of atherosclerosis and of increased cardiovascular risk, potentially useful as a therapeutic target in those at increased cardiovascular risk. The utilization of carotid IMT measurements as a surrogate end point in clinical trials evaluating a specific drug intervention may result in considerably smaller efforts and costs than when using a hard end point such as myocardial infarction, stroke, or death. In addition, the use of carotid IMT measurement as a screening tool in clinical practice in association with traditional risk factors may improve risk classification and decisions regarding therapeutic interventions. However, although carotid IMT may be correlated with clinical outcomes, changes in surrogate end points over time that result from a particular therapy may not necessarily be predictive of future cardiovascular events. Therefore, it is necessary to perform more clinical studies to clearly define the relationship between the modifications in carotid IMT and the changes in cardiovascular events. In an era of economic burden, when there is a clear combination of limited resources with high expense of innovation in drug development, carotid IMT represents a reasonable, worthwhile surrogate trial end point with a history of nearly 30 years of technical progress and clinical research. Current data strongly suggest that carotid IMT will continue to successfully be used as a valuable tool in clinical atherosclerosis research.

Changes in natriuretic peptides after acute hospital presentation for heart failure with preserved ejection fraction: A feasible surrogate trial endpoint? A report from the prospective Karen study

BackgroundIn acute decompensated heart failure (ADHF) with preserved ejection fraction (HFpEF) there are no surrogate endpoints for early phase trials. The aim of the current study was to evaluate whether a reduction in natriuretic peptides (NP) between acute hospital presentation to stable follow-up is associated with improved mortality and morbidity. MethodsPatients presenting acutely to the hospital for ADHF with HFpEF enrolled in the Karolinska Rennes (KaRen) study and reporting N-terminal pro-B-type NP or B-type NP assessment at baseline hospital presentation and at 4–8weeks follow-up were prospectively studied. Logistic regression analyses were performed to detect the predictors of baseline and changes in NPs. Cox regression models were performed to assess the impact of NP reductions on mortality and the composite of mortality and HF hospitalization. ResultsOf 361 patients (median follow-up 585days), 267 (74%) reported an improvement in NPs, while 94 (26%) reported worsening. At baseline, the independent predictors of lower NPs were higher glomerular filtration rate (Odds Ratio [OR] per unit: 1.013; 95% Confidence Interval [CI]: 1.005–1.021) and younger age (OR per year: 0.972; CI: 0.947–0.998). Improvement in NPs at follow-up was predicted by higher heart rate at baseline (OR per bpm: 1.014; CI: 1.003–1.025). After adjustments, the hazard ratio for all-cause death was 0.730 (CI: 0.456–1.169) and for the composite outcome 0.814 (CI: 0.582–1.139) for patients who improved vs. worsened in NP levels. ConclusionsIn patients presenting acutely to the hospital with HFPEF, an improvement in NP levels did not independently and significantly predict improved mortality and/or morbidity. NPs as surrogate endpoints in acute HFpEF require further study.

Surrogate Markers: Lessons from the Next Gen?

The article by Banerjee and colleagues published in this issue of the journal involving a randomized control prevention trial of ursodeoxycholic acid (UDCA) in Barrett esophagus reported a null outcome despite being well designed and executed. Possible reasons for this null outcome are discussed focusing on use of surrogate endpoints in the trial. The trial is especially topical because it comes at a time when there are calls for a Pre-Cancer Genome Atlas (PCGA) for "understanding the earliest molecular and cellular events associated with cancer initiation…" This commentary discusses current concepts in prevention research including branched evolution that leads to therapeutic resistance. Length bias sampling postulates underdiagnosis is due to rapidly progressing disease that is difficult to detect by screening because it progresses to cancer too rapidly and that overdiagnosis is the result of very slowly or nonprogressing disease that is easy to detect by screening because it persists for a lifetime and the patient dies of unrelated causes. Finally, it also explores study designs, including surrogate endpoints in Barrett esophagus trials, and opportunities and pitfalls for a PCGA in the context of high levels of over and underdiagnosis of Barrett esophagus as well as many other cancers and their precursors. Cancer Prev Res; 9(7); 512-7. ©2016 AACRSee related article by Banerjee, et al., p. 528.

Relevance of Changes in Serum Creatinine During a Heart Failure Trial of Decongestive Strategies: Insights From the DOSE Trial

BackgroundWorsening renal function (WRF) is a common endpoint in decompensated heart failure clinical trials because of associations between WRF and adverse outcomes. However, WRF has not universally been identified as a poor prognostic sign, challenging the validity of WRF as a surrogate endpoint. Our aim was to describe the associations between changes in creatinine and adverse outcomes in a clinical trial of decongestive therapies. Methods and ResultsWe investigated the association between changes in creatinine and the composite endpoint of death, rehospitalization or emergency room visit within 60 days in 301 patients in the Diuretic Optimization Strategies Evaluation (DOSE) trial. WRF was defined as an increase in creatinine >0.3 mg/dL and improvement in renal function (IRF) as a decrease >0.3 mg/dL. When examining linear changes in creatinine from baseline to 72 hours (the coprimary endpoint of DOSE), increasing creatinine was associated with lower risk for the composite outcome (HR = 0.81 per 0.3 mg/dL increase, 95% CI 0.67–0.98, P = .026). Compared with patients with stable renal function (n = 219), WRF (n = 54) was not associated with the composite endpoint (HR = 1.17, 95% CI = 0.77–1.78, P = .47). However, compared with stable renal function, there was a strong relationship between IRF (n = 28) and the composite endpoint (HR = 2.52, 95% CI = 1.57–4.03, P < .001). ConclusionThe coprimary endpoint of the DOSE trial, a linear increase in creatinine, was paradoxically associated with improved outcomes. This was driven by absence of risk attributable to WRF and a strong risk associated with IRF. These results argue against using changes in serum creatinine as a surrogate endpoint in trials of decongestive strategies.

Trends in Utilization of Surrogate Endpoints in Contemporary Cardiovascular Clinical Trials

Surrogate endpoints facilitate trial efficiency but are variably linked to clinical outcomes, and limited data are available exploring their utilization in cardiovascular clinical trials over time. We abstracted data regarding primary clinical, intermediate, and surrogate endpoints from all phase II to IV cardiovascular clinical trials from 2001 to 2012 published in the 8 highest Web of Science impact factor journals. Two investigators independently classified the type of primary endpoint. Of the 1,224 trials evaluated, 677 (55.3%) primary endpoints were clinical, 165 (13.5%) intermediate, and 382 (31.2%) surrogate. The relative proportions of these endpoints remained constant over time (p= 0.98). Trials using surrogate endpoints were smaller (187 vs 1,028 patients) and enrolled patients more expeditiously (1.4 vs 0.9 patients per site per month) compared with trials using clinical endpoints (p <0.001 for both comparisons). Surrogate endpoint trials were independently more likely to meet their primary endpoint compared to trials with clinical endpoints (adjusted odds ratio 1.56, 95% CI 1.05 to 2.34; p= 0.03). Rates of positive results in clinical endpoint trials have decreased over time from 66.1% in 2001 to 2003 to 47.2% in 2010 to 2012 (p= 0.001), whereas these rates have remained stable over the same period for surrogate (72.0% to 69.3%, p= 0.27) and intermediate endpoints (74.4% to 71.4%, p= 0.98). In conclusion, approximately a third of contemporary cardiovascular trials use surrogate endpoints. These trials are completed more expeditiously and are more likely to meet their primary outcomes. The overall scientific contribution of these surrogate endpoint trials requires further attention given their variable association with definitive outcomes.

Abstract 19637: Two Decades of Cardiovascular Trials With Primary Surrogate Endpoints: 1990- 2011

Background: Surrogate endpoint trials can test strategies more efficiently, but are accompanied by uncertainty about the relationship between changes in surrogate markers and clinical outcomes. We sought to determine recent trends in the publication of cardiovascular trials with surrogate outcomes. Methods: We identified cardiovascular trials with primary surrogate endpoints published in NEJM, Lancet, and JAMA from January 1990 to December 2011. Trends in publication of surrogate endpoint trials, and the success of the trials in meeting their primary endpoint were evaluated. We also tracked the above three journals for publication of clinical outcome trials on the interventions tested in surrogate trials. Results: We screened 3016 articles and identified 848 primary hypothesis cardiovascular trials, which included 220 surrogate endpoint trials. There was an increase over time in the number of surrogate endpoint trials (P=0.01). From the total of 220 surrogate trials, 157 (71.4 %) were positive for their primary endpoint. Sixty (27.5%) surrogate trials were followed by at least one clinical outcome trial. Among these 60 surrogate trials, in 24 cases the outcomes trial results validated the positive surrogates; whereas in 21 subsequent outcome trials were negative following positive results on a surrogate. However, we identified only 3 examples in which the surrogate trial was negative but a subsequent outcomes trial was conducted and showed benefit (Figure). Conclusions: Cardiovascular surrogate outcomes trials are common, frequently show superiority of the tested intervention and are infrequently followed by a prominent outcomes trial. However, when there was a high profile clinical outcomes study, half of the positive surrogate trials were not validated. Cardiovascular surrogate outcome trials may be more appropriate for excluding benefit from the patient perspective than for identifying it.

Progression-free survival as surrogate endpoint in advanced pancreatic cancer: meta-analysis of 30 randomized first-line trials

Progression-free survival (PFS) has not been extensively investigated as a surrogate for survival in the first-line treatments of pancreatic cancer. The aim of this review was to evaluate PFS as a potential surrogate endpoint for overall survival (OS) in advanced pancreatic cancer in trials comparing poly-chemotherapy to gemcitabine alone. A systematic literature search in PubMed, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials was conducted. The key words included randomized trial, first-line chemotherapy, pancreatic cancer, gemcitabine and poly-chemotherapy. Adjusted weighted linear regression was used to calculate RS (Spearman's rank-order correlation coefficient) between PFS and post-progression survival (PPS) with OS (RS) and between treatment effects on PFS and OS (RHR). A total of 30 trials including 8467 patients met the inclusion criteria. Correlation between the treatment effects on PFS and OS (RHR=0.78) and between the endpoint PFS and OS was high across all studies (RS=0.75). The slope of the regression line was 0.76+/-0.26, indicating that an agent producing a 10% risk reduction for PFS will provide a 7.6%+/-2.6% risk reduction for OS. Correlation between PPS and OS was very strong (RS=0.71) and accounted for more than 50% of the whole OS variability (R2=0.57). Because of the robust correlation with OS and the potential influence of PPS caused by the second line therapies, it may be justified to consider PFS as a surrogate endpoint in trials evaluating new cytotoxic agents when gemcitabine is the control arm.

Radiographic progression by Prostate Cancer Working Group (PCWG)‐2 criteria as an intermediate endpoint for drug development in metastatic castration‐resistant prostate cancer

To investigate the association of radiographic progression defined by Prostate Cancer Working Group (PCWG)-2 guidelines and overall survival (OS) in men with metastatic castration-resistant prostate cancer (mCRPC). Two trials that used PCWG-2 guidelines to define progression were analysed: a randomized phase II trial (n = 221) comparing first-line docetaxel-prednisone plus AT-101 or placebo, and a phase III trial (n = 873) comparing prednisone plus sunitinib or placebo after docetaxel-based chemotherapy. Cox proportional hazards regression models were used to estimate the association of radiographic progression with OS. Landmark analyses compared progressing patients with those who had not progressed. Sub-analyses compared patients removed from trial for progression vs other reasons. An increased risk of death was seen for radiographic progression at landmark times from 6 to 12 months with docetaxel-based therapy (hazard ratio [HR] >1.7 at all time-points). An increased risk of death was also seen with post-docetaxel prednisone alone or with sunitinib for progression at landmark times from 2 to 8 months (HR >2.7 at all time-points). Kendall's τ was 0.50 (P < 0.001) in the setting of docetaxel-based therapy and 0.34 (P < 0.001) in the post-docetaxel setting for association between radiographic progression and death amongst patients with both events. Removal from study due to radiographic progression was associated with a significantly lower OS compared with removal for other reasons in both trials. Limitations of a retrospective analysis apply and there was no central radiology review. Radiographic progression by PCWG-2 criteria was significantly associated with OS in patients with mCRPC receiving first-line docetaxel-based chemotherapy or post-docetaxel therapy. With external validation as a surrogate endpoint in trials showing survival benefits, the use of radiographic progression-free survival may expedite drug development in mCRPC, which has been hampered by the lack of intermediate endpoints.

Future of High-Density Lipoprotein Infusion Therapies

The field of high-density lipoprotein (HDL) therapeutics is broadly aimed at combating the significant residual cardiovascular risk remaining after effective low-density lipoprotein (LDL) cholesterol reduction.1 After the recent failure of 3 orally active HDL-raising agents in prospective intervention trials, including 2 in the cholesteryl ester transfer protein (CETP) inhibitor class2,3 and niacin,4,5 the goals of HDL therapy are currently undergoing reassessment. Key opinion leaders are advocating a shift in the target of HDL therapy from elevation in circulating HDL cholesterol levels to enhancement of the functional properties of HDL, especially HDL-mediated reverse cholesterol transport and cellular cholesterol efflux.6,7 These events have focused the spotlight on HDL infusion therapies that transiently increase HDL particle number and enhance efflux capacity for cellular cholesterol; other defective features of HDL functionality may potentially be normalized.8 However, evaluation of HDL infusion therapies has been limited to date to small surrogate end-point trials; indeed, large phase 3 outcome trials to test the efficacy of these agents in reducing definitive morbidity and mortality end points are eagerly awaited. If proven effective, HDL infusion agents would have potential application across a wide range of vascular diseases but would be particularly amenable to delivery in the context of acute coronary syndromes. Coronary artery disease morbidity and mortality relate largely to either physical disruption or endothelial erosion of the fibrous cap of atherosclerotic plaques in the coronary arteries, triggering luminal or intraplaque thrombus formation.9 An acute or unstable coronary syndrome (sudden death, nonfatal myocardial infarction, or unstable angina) results, the nature of which depends in large part on the degree of vessel occlusion. Plaques at greatest risk for rupture are characterized by a marked abundance of both extracellular and intracellular lipid (cholesterol); immunoinflammatory cells, including monocyte-macrophages and T …

Surrogate Endpoint Analysis: An Exercise in Extrapolation

Surrogate endpoints offer the hope of smaller or shorter cancer trials. It is, however, important to realize they come at the cost of an unverifiable extrapolation that could lead to misleading conclusions. With cancer prevention, the focus is on hypothesis testing in small surrogate endpoint trials before deciding whether to proceed to a large prevention trial. However, it is not generally appreciated that a small surrogate endpoint trial is highly sensitive to a deviation from the key Prentice criterion needed for the hypothesis-testing extrapolation. With cancer treatment, the focus is on estimation using historical trials with both surrogate and true endpoints to predict treatment effect based on the surrogate endpoint in a new trial. Successively leaving out one historical trial and computing the predicted treatment effect in the left-out trial yields a standard error multiplier that summarizes the increased uncertainty in estimation extrapolation. If this increased uncertainty is acceptable, three additional extrapolation issues (biological mechanism, treatment following observation of the surrogate endpoint, and side effects following observation of the surrogate endpoint) need to be considered. In summary, when using surrogate endpoint analyses, an appreciation of the problems of extrapolation is crucial.

The Risky Reliance on Small Surrogate End Point Studies When Planning a Large Prevention Trial

The definitive evaluation of treatment to prevent a chronic disease with low incidence in middle age, such as cancer or cardiovascular disease, requires a trial with a large sample size of perhaps 20,000 or more. To help decide whether to implement a large true endpoint trial, investigators first typically estimate the effect of treatment on a surrogate endpoint in a trial with a greatly reduced sample size of perhaps 200 subjects. If investigators reject the null hypothesis of no treatment effect in the surrogate endpoint trial they implicitly assume they would likely correctly reject the null hypothesis of no treatment effect for the true endpoint. Surrogate endpoint trials are generally designed with adequate power to detect an effect of treatment on surrogate endpoint. However, we show that a small surrogate endpoint trial is more likely than a large surrogate endpoint trial to give a misleading conclusion about the beneficial effect of treatment on true endpoint, which can lead to a faulty (and costly) decision about implementing a large true endpoint prevention trial. If a small surrogate endpoint trial rejects the null hypothesis of no treatment effect, an intermediate-sized surrogate endpoint trial could be a useful next step in the decision-making process for launching a large true endpoint prevention trial.

Circulating Tumor Cells Move One Step Closer to Use as Surrogate Trial Endpoint in Prostate Cancer

Circulating Tumor Cells Move One Step Closer to Use as Surrogate Trial Endpoint in Prostate Cancer

Can circulating tumour cells be used as surrogate trial endpoint in prostate cancer treatment?

Can circulating tumour cells be used as surrogate trial endpoint in prostate cancer treatment?

New Lipid Modulating Drugs: The Role of Microsomal Transport Protein Inhibitors

Microsomal triglyceride transfer protein (MTP) is involved in the synthesis of very low density lipoprotein in the liver. Its deficiency results in abetalipoproteinemia. MTP inhibitors target the assembly and secretion of apolipoprotein B-containing lipoproteins. These agents may potentially play a role, alone or in combination, in the treatment of hypercholesterolemia or hypertriglyceridaemia. Clinical applications of MTP inhibitors initially focused primarily on high-dose monotherapy in order to produce substantial reductions in LDL-cholesterol levels but these proved to induce significant hepatic steatosis and transaminase elevations. However, likely orphan indications for MTP inhibitors, where a different risk-benefit profile applies, include patients with homozygous familial hypercholesterolemia where statins often show a low response. Development of MTP inhibitors has continued to enter clinical trials at lower doses or in formulations aimed at utilizing their efficacy while avoiding their side effects. These have shown promising results in reducing cholesterol, triglycerides and apolipoprotein B with a far lower incidence of, often, transient side-effects. The clinical efficacy and safety of MTP inhibition in patients with hyperlipidaemia remains to be fully determined and to be proven in both surrogate and clinical endpoint trials but there may be a role for these agents in orphan indications for rarer severe hyperlipidaemias.

Meta-regression of CIMT trials—data in, garbage out

Meta-regression of trials using carotid intima–media thickness (CIMT) as a surrogate end point leads to unreliable results owing to heterogeneity in methods, interventions, and outcomes of pooled trials. CIMT will continue to be a worthwhile surrogate trial end point supported by two decades of technical progress and clinical atherosclerosis research.

Adjunctive Lipid Lowering Therapy in the Era of Surrogate Endpoints

Statins have been shown to reduce cardiovascular events. However, despite widespread use of statin therapy, residual cardiovascular risk remains, and this has left clinicians searching for an effective adjunctive therapy to optimize lipid profiles and reduce risk further. Given the cost and duration of large event driven trials, adjunctive lipid lowering therapy options have largely been evaluated through surrogate measures of atherosclerosis, making clinical practice decisions regarding combination therapy difficult. Two common approaches that have been evaluated almost entirely by surrogate outcome trials include the addition of ezetimibe or the addition of niacin. Our article attempts to place these surrogate end point trials in their proper context, providing clinicians with a practical approach to making clinical practice decisions regarding adjunctive therapy in the absence of clinical outcomes data. Although definitive changes to lipid lowering guidelines should be based on clinical outcomes trials, in the absence of clinical outcomes data, it is reasonable to make individualized clinical practice decisions on the basis of surrogate measures of disease as long as there is corroboration among the effect on atherosclerosis and lipid parameters as adjunctive therapy, and clinical outcomes as monotherapy. Given that niacin fits these criteria, it seems prudent to support the use of niacin as adjunctive therapy in combination with maximally tolerated dose of statin in patients with low high-density lipoprotein-cholesterol and known coronary artery disease. Three ongoing clinical outcomes trials evaluating niacin and ezetimibe in combination with statin will provide more definitive word regarding the safety and efficacy of these agents as adjunctive therapy.