Study To Evaluate Cardiac Assessments Following Different Treatments Of Smoking Cessation Medications In Subjects With And Without Psychiatric Disorders.: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study To Evaluate Cardiac Assessments Following Different Treatments Of Smoking Cessation Medications In Subjects With And Without Psychiatric Disorders. (NCT01574703), a randomized phase 4 study. The primary outcome is Time to Occurrence of Major Adverse Cardiovascular Event (MACE) During Treatment Period (up to Date of Last Dose of Study Drug) in Study NCT01456936..

2. Clinical Question

3. Trial Design

This is a phase 4 record for a non-treatment follow-up study of cardiovascular assessments after smoking-cessation treatment. The registry gives an enrollment of 4595 and identifies the study as completed. Its brief summary says the follow-up was intended to collect cardiovascular safety data for participants in study A3051123 for an additional 28 weeks, for a total of 52 weeks of cardiovascular safety data collection.

The registry lists random allocation, no masking, and a single-group model. It names placebo, varenicline tartrate, bupropion hydrochloride, and a nicotine replacement therapy patch as interventions. The clinical results include treatment groups from the parent study, but the follow-up itself is described as non-treatment. The registry record does not explain how the single-group model relates to the treatment-group results or provide arm-specific descriptions.

The recorded study start is 2012-05, and primary completion is 2015-07. The primary outcome’s timeframe is baseline to the last dose of study drug in parent study NCT01456936, up to 12 weeks. Other outcomes extend assessment to 30 days after the last dose or through the end of the follow-up study. These are different observation windows and should not be treated as interchangeable. The record does not report a sample-size justification, detailed follow-up procedures, or a statistical analysis plan.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Before assignment: This is a non-treatment extension study of parent study NCT01456936. No study drug was provided in this extension phase. However, cardiovascular events that occurred during parent study NCT01456936 when participants received varenicline(N=2016), bupropion(N=2006),NRT(N=2022), or placebo(N=2014) in a triple-dummy design were analyzed in this study.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The safety analysis set is defined as all participants that received at least one partial dose of study drug during the parent study NCT01456936.

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

Population: The term Baseline visit refers to the Baseline (Week 0) visit of the parent study NCT01456936. The safety population included all participants who received at least one dose of study drug in NCT01456936 parent study. The below Baseline characteristics (age, gender) are presented for all participants who entered study NCT01574703.

6. Primary Endpoint

The registry lists the primary outcome as Time to Occurrence of Major Adverse Cardiovascular Event (MACE) During Treatment Period (up to Date of Last Dose of Study Drug) in Study NCT01456936., measured over Baseline to last dose of study drug in parent study NCT01456936 (up to 12 weeks)..

The primary endpoint is time to occurrence of an adjudicated major adverse cardiovascular event during the treatment period of parent study NCT01456936. MACE is defined as cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. The stated observation window runs from baseline to the last dose of study drug, up to 12 weeks. The registry describes the outcome as a hazard ratio relative to placebo, with a 95% confidence interval.

A time-to-event endpoint incorporates both whether an event occurred and when it occurred during the specified observation period. It can also account for participants whose event status is not observed through the end of follow-up, depending on censoring and analysis procedures. Those procedures are not reported in the registry record, so the handling of incomplete observation cannot be assessed from this description alone.

Adjudication indicates that events are evaluated against the endpoint definition, but the registry does not describe the adjudication process. Cardiovascular death, myocardial infarction, and stroke are combined in the composite; the primary result therefore concerns time to the first qualifying MACE event as analyzed, rather than providing separate estimates for each component. The endpoint is used to assess cardiovascular safety over the treatment window, but the posted results do not establish what would happen beyond the observation periods recorded.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

How should a hazard ratio be read?

A hazard ratio compares the event rate over time between groups, under the assumptions of the fitted time-to-event approach. A value of 1 represents equal hazards; a value below 1 indicates a lower estimated hazard in the named treatment group relative to the reference, and a value above 1 indicates a higher estimated hazard. It is not a ratio of the total number of events and should not be read directly as an absolute risk difference.

For the primary endpoint, placebo is the reference for the reported treatment hazard ratios. The confidence intervals communicate uncertainty around each estimate. Because the intervals include 1, the data do not rule out equal hazards under the usual interpretation of these intervals. Their breadth also means that the estimates do not pinpoint the magnitude or direction of any difference with precision.

What does the log-rank analysis contribute?

The log-rank test compares time-to-event experience across groups over the observation period. The registry reports a single p-value of 0.37 for the analysis across the treatment groups. This is an overall test, not a separate p-value for every treatment versus placebo. A p-value describes how unusual data at least as inconsistent with the null hypothesis would be under that hypothesis and the test’s assumptions. It is not the probability that the null hypothesis is true, nor does it measure the size or clinical importance of an effect.

The registry names the method but does not report details such as the handling of censoring, the timing of events, or checks of model assumptions. Those omissions limit independent assessment of the time-to-event analysis. A confidence interval and p-value also do not correct for weaknesses in endpoint ascertainment or incomplete follow-up.

How do the binary recalculations differ?

For some secondary binary outcomes, recalculations use the posted event counts and denominators to estimate an unadjusted risk difference between two groups. A risk difference is the difference in the observed proportions, expressed on the scale used for the calculation. Its confidence interval describes uncertainty around that contrast. When the interval includes zero, the raw summary data do not establish a difference at the corresponding confidence level.

These simple recalculations do not incorporate covariate adjustment or other modeling unless explicitly stated; the record does not supply adjusted estimates for these recalculations. They are not necessarily the same estimand or method as the sponsor’s logistic regression analyses. Sparse event counts can make binary estimates unstable and confidence intervals broad. In general, when events are rare, a small change in the event count can substantially alter a proportion or relative estimate. That is a statistical reason to avoid treating rounded percentages as precise measurements.

The posted sponsor analyses for selected secondary outcomes report logistic regression risk differences, confidence intervals, and p-values. They involve treatment comparisons that differ from the recalculated comparisons against placebo. The registry does not give enough methodological detail to establish why estimates differ or whether the sponsor’s models included covariates. Interpret them as separately reported analyses, not as a correction or validation of the raw recalculations.

What do planning illustrations mean?

Planning illustrations based on an observed effect estimate the participants per arm that would be needed under stated assumptions: a two-sided significance level of 0.05, equal allocation, a normal approximation, and an effect set to a stated fraction of the observed effect. They are hypothetical design calculations, not observed trial results and not observed power. The event-based illustrations use total events for time-to-event outcomes; the other illustrations use participants per arm. When the observed effect is very close to zero, calculations that attempt to detect a fraction of that effect can become extremely large and should not be treated as realistic design recommendations.

These calculations do not replace the study’s original sample-size rationale. That rationale is not reported in the registry record. They also do not establish whether the study was adequately powered for cardiovascular safety, especially when event rates are low and estimates are imprecise.

10. Analyses Reported by the Sponsor

The registry’s sponsor-reported primary analysis is the log-rank comparison across the treatment groups, with p = 0.37. The hazard ratios and confidence intervals are also posted for each active treatment relative to placebo. There is no recalculated primary time-to-event analysis in the posted results, so the primary finding is described from the registry’s reported analysis.

For selected secondary binary outcomes, the registry reports logistic regression risk differences. For incidence of MACE during treatment, the reported comparison of varenicline with bupropion is -0.49, with a 95% confidence interval from -5.22 to 4.23 and p = 0.838; the reported varenicline versus NRT comparison is -0.07, with a 95% confidence interval from -5.20 to 5.05 and p = 0.978. The record reports other logistic regression estimates for selected secondary outcomes as well.

The simple recalculations use raw event counts and denominators and compare selected active-treatment groups with placebo. Thus they differ both in method and, in some cases, in comparison. The registry does not explain the differences between the sponsor’s reported estimates and the unadjusted calculations, and it does not provide enough model detail to attribute those differences to a particular adjustment or analytic choice. These results should not be treated as interchangeable. The sponsor-reported analyses remain the registry’s own analyses; the raw recalculations are descriptive checks rather than replacements.

11. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary time-to-MACE endpoint and eight secondary outcomes. Several secondary measures concern MACE or MACE+ over overlapping time windows, and some are time-to-event outcomes while others are incidence outcomes. When many outcomes and comparisons are examined, the chance of at least one apparently unusual result can increase. Adjusting for multiplicity or specifying an outcome hierarchy can help control how such evidence is interpreted. A multiplicity plan is not reported in the registry record, so it is not possible to determine whether the posted secondary analyses were adjusted or how confirmatory they were intended to be.

Missing-data handling is also not reported in the registry record. For a time-to-event outcome, participants may have incomplete observation; how censoring, withdrawal, and loss to follow-up were handled affects interpretation. The record does not state the assumptions used for censoring, describe imputation, or provide outcome-specific completeness information. It is therefore not possible to assess whether missing outcome data could have altered the estimates.

The primary outcome description identifies a safety analysis set consisting of participants who received at least one partial dose of study drug in parent study NCT01456936. That definition is useful, but the registry does not provide a full account of analysis populations for each secondary outcome or clarify whether all listed denominators correspond to the same population. The number enrolled in the follow-up and the treatment-group denominators displayed for particular outcomes refer to different record elements; the registry does not explain their relationship. No inference about exclusions or participant flow should be made from those figures alone.

The registry record also does not report interim analyses, a sample-size justification, or a complete statistical analysis plan. Those omissions leave key questions about planned testing, precision targets, and analysis decisions unresolved. In particular, the planning illustrations based on observed effects do not document the study’s original design assumptions.

12. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: acute myocardial infarction (0.3%), pneumonia (0.3%), atrial fibrillation (0.2%), gallbladder disorder (0.2%), asthma (0.2%).

The serious adverse event summaries list participants at risk and participants affected for each treatment group. The reported at-risk and affected counts are 1192 and 34 for varenicline, 1166 and 39 for bupropion, 1116 and 43 for the NRT patch, and 1121 and 41 for placebo. These are descriptive counts; they are not, by themselves, comparative estimates or evidence of a treatment effect. The registry does not report inferential comparisons for these serious adverse event counts.

The listed serious-event terms include acute myocardial infarction and pneumonia at 0.3% each, and atrial fibrillation, gallbladder disorder, asthma, and congestive cardiac failure at 0.2% each. These are the terms identified among the most common serious events in the record, not a complete account of all events or a direct comparison among groups. The registry does not report death counts in this safety summary. The serious adverse event observation window and detailed definitions are not stated in the posted safety figures, so they should not be assumed to match the primary endpoint window.

Serious adverse event counts and the adjudicated MACE endpoint are related safety information but are not interchangeable measures. The event terms may include conditions outside the MACE definition, and the registry does not state that every MACE event appears in the serious-event summary. These data are descriptive context, not a standalone basis for concluding that a treatment is safer or less safe.

13. What the Result Does, and Does Not, Mean

The posted primary results describe estimated time-to-MACE hazards relative to placebo during the parent study’s treatment period. The point estimates are below 1 for each active treatment, but their confidence intervals are wide and include 1. The overall log-rank p-value is 0.37. Together, these results do not establish a statistically significant difference among the groups, and they do not demonstrate equivalence or exclude meaningful differences.

The findings are specific to the endpoint definition and observation window. MACE combines cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke, and the primary timeframe ends at the last dose of study drug in the parent study, up to 12 weeks. The follow-up study’s broader aim was to collect cardiovascular safety data for a longer period, but the primary endpoint result does not itself summarize every later event or all outcomes through the end of follow-up.

The registry title refers to people with and without psychiatric disorders, but the posted result does not give separate estimates by psychiatric history. It therefore cannot answer whether the cardiovascular results differed between those subgroups. Nor does the primary analysis compare smoking-cessation success or establish the effectiveness of the treatments for cessation. This is a cardiovascular safety result, not a complete assessment of all benefits and harms.

Finally, the precision and interpretability of the results are limited by sparse-event summaries and missing methodological detail. The registry does not describe missing-data procedures, censoring assumptions, or a multiplicity plan. Those gaps mean that the estimates should be read as the results recorded for the stated analyses, not as definitive evidence that risks are identical across treatments or that all possible cardiovascular risks have been ruled out.

14. Why This Trial Matters Statistically

This trial is statistically important because cardiovascular safety questions often involve events that occur infrequently, while comparisons need to distinguish treatment-related differences from random variation. The primary endpoint uses time-to-event information and a clinically defined composite, and the registry presents hazard ratios with confidence intervals rather than relying only on a single significance test. The intervals make the uncertainty visible: the estimates are not precise enough to settle the direction or magnitude of differences.

The study also illustrates why a non-significant test is not evidence of equivalence. A p-value of 0.37 does not show that the treatments have identical cardiovascular effects. The wide intervals permit a range of possibilities, which is a central limitation when rare events yield limited information. Interpreting the point estimates without their uncertainty would overstate what the data can support.

Several additional outcomes look at events during treatment and across longer windows. Their overlap shows the value and difficulty of collecting extended safety information: broader follow-up may capture events missed in a short treatment window, but multiple related analyses complicate interpretation. Without a reported multiplicity strategy and detailed analysis plan, secondary results should be treated as supportive or descriptive rather than as separate definitive tests.

The record also demonstrates the importance of distinguishing sponsor-reported models from transparent raw-data recalculations. Logistic regression estimates and unadjusted risk differences can answer related but non-identical questions. Keeping the methods and comparison groups explicit helps prevent unlike estimates from being read as if they were directly interchangeable. For clinicians and researchers, the key statistical lesson is to assess endpoint, follow-up, population, and precision together, rather than treating a point estimate or p-value as a complete summary.

15. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The registry record gives limited detail about how the follow-up study was conducted and analyzed. It lists randomized allocation and no masking, but also describes a single-group model while posting results for parent-study treatment groups. It does not explain that combination or provide arm descriptions. The record identifies the study as a non-treatment extension, so the treatment-group comparisons should be understood in the context of the parent study rather than as evidence that participants were newly randomized to treatments in this follow-up.

The primary result concerns the treatment period in parent study NCT01456936, whereas the extension’s purpose was to collect cardiovascular safety data for longer. The registry lists several timeframes, but does not fully describe how participants were followed across them or how events occurring after treatment were handled. The relationship between the enrollment figure for the follow-up and the endpoint-specific treatment-group denominators is not explained in the record.

Important analytic details are absent: the sample-size rationale, censoring and missing-data procedures, model assumptions, adjudication procedures, interim analyses, and multiplicity plan are not reported. The primary safety analysis population is described, but outcome-specific population details are limited. The registry also does not provide subgroup estimates despite the title’s reference to psychiatric history. These gaps limit assessment of robustness and generalizability.

Finally, rare events yield imprecise comparisons, and several secondary outcomes involve overlapping definitions or time windows. The posted secondary analyses are not comprehensive pairwise comparisons, and sponsor-reported logistic regression results do not use the same comparisons as all raw recalculations. These limitations constrain conclusions about relative safety and make it inappropriate to interpret a lack of statistical significance as proof of no difference.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Study To Evaluate Cardiac Assessments Following Different Treatments Of Smoking Cessation Medications In Subjects With And Without Psychiatric Disorders. — NCT01574703.
• Registry record last updated 2016-12-29; status last verified 2016-10.
• Results first posted 2016-12-29.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

19. Record Summary

NCT01574703 is a completed phase 4 non-treatment follow-up focused on cardiovascular safety after smoking-cessation treatments. The registry gives an enrollment of 4595 and describes an additional 28 weeks of safety data collection intended to support a total of 52 weeks. The primary endpoint is time to adjudicated MACE during treatment in parent study NCT01456936, with hazard ratios reported relative to placebo.

The log-rank p-value is 0.37. The treatment hazard-ratio confidence intervals are wide and include 1, so the primary results do not establish a difference and do not demonstrate equivalence. Secondary results cover MACE and MACE+ across several periods, with selected sponsor logistic regression analyses and unadjusted recalculations. Missing-data methods, multiplicity procedures, sample-size justification, and several other analysis details are not reported in the registry record.