This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record.
1. Trial at a Glance
ONTARGET was a large randomized, parallel-group prevention trial in patients at high risk for cardiovascular events. It asked two different statistical questions at once: whether telmisartan alone was non-inferior to ramipril, and whether combining telmisartan with ramipril was superior to ramipril alone. Patients who could not tolerate ramipril were entered into TRANSCEND, a placebo-controlled comparison of telmisartan.
| Feature | ONTARGET (NCT00153101) |
|---|---|
| Phase | Phase 4 |
| Condition | Cardiovascular diseases; patients at high risk for cardiovascular events |
| Primary purpose | Prevention |
| Design model | Parallel-group, randomized |
| Interventions | Telmisartan; combination of telmisartan and ramipril; ramipril |
| Companion trial | TRANSCEND: telmisartan vs placebo in patients intolerant to ramipril |
| Enrollment | 31,546 |
| Primary endpoints | Cardiovascular composite (ONTARGET); renal composite in diabetic nephropathy (ONTARGET); cardiovascular composite (TRANSCEND) |
| Time frame | 56 months |
| Dates | Start November 2001; primary completion June 2008; status completed |
| Sponsor | Boehringer Ingelheim (industry) |
2. Clinical Question
ONTARGET was built around a comparison with an established active treatment. Ramipril served as the reference therapy, and the trial asked whether an alternative drug (telmisartan) could preserve its effect on major cardiovascular events, and whether adding telmisartan on top of ramipril could improve on it. TRANSCEND addressed a different, placebo-controlled question for patients who could not take ramipril at all.
Population
Patients at high risk for cardiovascular events. Those intolerant to ramipril were entered into TRANSCEND instead. The renal primary endpoint was assessed in the subset with diabetic nephropathy (diabetes with macro-albuminuria, UACR ≥300 mg/g creatinine at baseline).
Intervention
Telmisartan 80 mg daily alone, or telmisartan 80 mg daily combined with ramipril 10 mg daily.
Comparator
Ramipril 10 mg daily in ONTARGET; placebo in TRANSCEND.
Primary question
Is telmisartan non-inferior to ramipril, and is the combination superior to ramipril, for time to first cardiovascular death, non-fatal myocardial infarction, non-fatal stroke or hospitalization for congestive heart failure?
3. Trial Design
ONTARGET: three parallel arms
Ramipril
- Ramipril 10 mg daily
- Telmisartan-matching placebo
- Comparator for both active-arm contrasts
Telmisartan
- Telmisartan 80 mg daily
- Ramipril-matching placebo
- Tested against ramipril with a margin of 1.13
Telmisartan + ramipril
- Telmisartan 80 mg daily
- Ramipril 10 mg daily
- Tested against ramipril for superiority
Telmisartan vs placebo
- Patients intolerant to ramipril
- Telmisartan compared with placebo
- Tested for superiority
The arm sizes shown above are the numbers of participants at risk in the serious-adverse-event tables of the ClinicalTrials.gov record. They describe the safety population rather than the randomized totals by arm, which the registry summary does not break down; the overall enrollment across both trials is 31,546.
4. Analysis Populations
All posted efficacy analyses use a Full Analysis Set (FAS) or a defined subset of it. The choice of population is not a technicality here: in a non-inferiority comparison, the analysis population can change the direction of bias.
| Analysis population | Definition in the registry | Used for |
|---|---|---|
| FAS of ONTARGET | Full Analysis Set of the ONTARGET trial | Cardiovascular primary endpoint; most secondary endpoints |
| FAS [DN] | All randomised patients with diabetic nephropathy (UACR ≥300 mg/g creatinine) of the ONTARGET trial | Renal primary endpoint; renal components in diabetic nephropathy |
| FAS of TRANSCEND | Full Analysis Set of the TRANSCEND trial | TRANSCEND primary endpoint |
| Patients without baseline diabetes | ONTARGET patients treated with the randomized regimens for 56 months without baseline diabetes | Newly diagnosed diabetes |
| Patients with baseline MMSE | ONTARGET patients treated with the randomized regimens with a Mini Mental State Examination at baseline | Cognitive decline |
A full analysis set is generally intended to be as close as possible to the intention-to-treat ideal of analysing every randomized patient in the group to which they were assigned. The FAS [DN] population is a subgroup defined by a baseline characteristic (albuminuria), so randomization is preserved within it; however, it is a much smaller population than the full trial, which is reflected in the wider confidence intervals for the renal endpoints.
5. Endpoints
Primary endpoints
| Endpoint | Registry definition | Time frame |
|---|---|---|
| ONTARGET cardiovascular composite | Time to first event analysis of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke and hospitalization for congestive heart failure. | 56 months |
| ONTARGET 3-fold renal composite in diabetic nephropathy | Doubling of serum creatinine, progression to end stage renal disease (ESRD) and all-cause mortality in diabetic nephropathy patients. ESRD is defined by initiation of dialysis, need for renal transplantation, or eGFR <15 mL/min/1.73 m². Diabetic nephropathy patients are diabetic patients with macro-albuminuria (UACR ≥300 mg/g creatinine) at baseline. These renal outcomes were not adjudicated (apart from death). | 56 months |
| TRANSCEND cardiovascular composite | Time to first event analysis of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke and hospitalization for congestive heart failure, in ACE-inhibitor-intolerant patients with cardiovascular disease. | 56 months |
Secondary endpoints with posted analyses
- Composite of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke
- Individual components: cardiovascular death; non-fatal myocardial infarction; non-fatal stroke; hospitalization for congestive heart failure
- Renal components in diabetic nephropathy: doubling of serum creatinine; progression to ESRD; all-cause mortality
- Renal outcomes in the full ONTARGET population: doubling of serum creatinine; progression to ESRD; new microalbuminuria; new macroalbuminuria; a combined renal endpoint; normalisation to normoalbuminuria
- Newly diagnosed congestive heart failure; cardiovascular revascularization procedure; newly diagnosed diabetes; cognitive decline
6. Statistical Methodology
Cox proportional-hazards regression
Every posted analysis of a time-to-event endpoint in ONTARGET and TRANSCEND uses Cox regression, reporting a hazard ratio with a confidence interval and a p-value. The Cox model estimates the ratio of instantaneous event rates between two groups without requiring any assumption about the shape of the underlying hazard over time.
Here h0(t) is an unspecified baseline hazard and β is the log hazard ratio for treatment. The model assumes the ratio of hazards is constant across follow-up (proportional hazards). The ClinicalTrials.gov record does not report covariates, stratification factors, or checks of the proportional-hazards assumption.
Each comparison is pairwise against ramipril
ONTARGET has three arms, but each posted analysis compares one arm with ramipril: telmisartan versus ramipril, and telmisartan plus ramipril versus ramipril. No direct telmisartan versus combination analysis is posted as a primary comparison. Ramipril is therefore the anchor for both questions, and each contrast has its own hypothesis type.
Non-inferiority framework
For the telmisartan versus ramipril comparison on the cardiovascular composite, the registry records the hypothesis as non-inferiority with a margin of 1.13 on the hazard-ratio scale, and reports a 97.5% confidence interval rather than a 95% interval.
Conclude non-inferiority if the upper confidence limit < 1.13
The margin expresses the largest relative increase in the hazard of the composite that would still be regarded as preserving an acceptable proportion of ramipril's effect. A margin of 1.13 tolerates, at most, a 13% higher estimated hazard with telmisartan.
Superiority framework
For the combination versus ramipril, for the renal primary endpoint, for TRANSCEND, and for nearly all secondary endpoints, the registry records a superiority hypothesis: the null hypothesis is HR = 1, and the question is whether the confidence interval excludes 1.
Chi-squared test and risk ratio for cognitive decline
Cognitive decline is the one posted endpoint analysed as a binary outcome rather than a time to event. The registry reports a risk ratio with a chi-squared test. A risk ratio compares the proportions of patients with the outcome at the end of the assessment period and does not use information about when the outcome occurred.
7. Primary Results: ONTARGET Cardiovascular Composite
The primary cardiovascular composite was analysed in the FAS of ONTARGET using Cox regression, with separate hypotheses for the two active comparisons.
7.1 Telmisartan vs ramipril (non-inferiority)
Hazard ratio, telmisartan vs ramipril
97.5% CI: 0.93–1.10 · P = 0.0019
Hypothesis: non-inferiority; margin 1.13
What the estimate means. An HR of 1.01 indicates that the estimated hazard of the composite with telmisartan was essentially the same as with ramipril: a 1% higher estimated hazard, which is a negligible difference.
What the interval says. The 97.5% CI of 0.93–1.10 is compatible with anything from a 7% lower to a 10% higher hazard with telmisartan. Because its upper limit (1.10) lies below the prespecified margin of 1.13, the data exclude the degree of harm that was defined as unacceptable. That is the formal basis for non-inferiority.
What it does not mean. Non-inferiority is not equivalence and is not superiority. The result does not show that telmisartan and ramipril are identical, and it does not rule out a hazard up to 10% higher. The conclusion is only as meaningful as the margin: a reader who would regard a 10% increase as clinically important should interpret the result with that in mind.
Why the p-value is not the effect size. P = 0.0019 tests the non-inferiority null hypothesis (HR ≥ 1.13), not the usual null of no difference. It is small because the interval sits clearly below the margin, not because telmisartan had a large effect. The registry does not state whether this p-value is one-sided or two-sided; in non-inferiority testing the hypothesis is inherently one-directional.
Why a 97.5% interval. A 97.5% interval is wider than a 95% interval and corresponds to a stricter error rate. Trials with more than one primary comparison commonly use a narrower alpha per comparison; the registry records the interval level but not the rationale. Using a wider interval makes the non-inferiority test harder to pass, so the conclusion is conservative in that respect.
Cautions. In a non-inferiority trial, poor adherence, crossover between treatments or lack of assay sensitivity all tend to make arms look similar and so favour a non-inferiority conclusion. A full-analysis-set result is therefore usually read alongside a per-protocol analysis; the registry reports the FAS analysis. The single hazard ratio also assumes that the relative hazard was roughly constant over the 56-month time frame.
7.2 Telmisartan + ramipril vs ramipril (superiority)
Hazard ratio, combination vs ramipril
95% CI: 0.92–1.07 · P = 0.8462
Hypothesis: superiority
What the estimate means. An HR of 0.99 corresponds to a 1% lower estimated hazard of the composite with the combination, which is effectively no difference from ramipril alone.
What the interval says. The 95% CI of 0.92–1.07 is narrow, reflecting the size of the trial. It is compatible with at most an 8% lower hazard and at most a 7% higher hazard. Because the interval includes 1, superiority was not demonstrated. Because it is also narrow, the data argue against any large benefit of adding telmisartan to ramipril for this composite.
What it does not mean. A non-significant superiority test does not by itself prove that the two regimens are equivalent. The posted hypothesis for this comparison was superiority, and no non-inferiority or equivalence test is posted for it. The narrow interval, however, does make a clinically important benefit on this endpoint implausible.
Why the p-value is not the effect size. P = 0.8462 means the observed HR is very close to what would be expected if the combination had no effect; it does not measure how large any effect is. The confidence interval carries that information.
Cautions. The comparison adds a second drug to an active background, so any added benefit had to be detected on top of ramipril's own effect. Interpretation of the combination should also consider its safety profile (Section 11) and its renal secondary results (Section 10), rather than the primary composite alone.
8. Primary Results: Renal Composite in Diabetic Nephropathy
The second ONTARGET primary endpoint was the 3-fold composite of doubling of serum creatinine, progression to ESRD and all-cause mortality, analysed in the FAS [DN] population of randomized patients with diabetic nephropathy. Both active arms were compared with ramipril under superiority hypotheses.
| Comparison | HR | 95% CI | P-value | Hypothesis |
|---|---|---|---|---|
| Telmisartan + ramipril vs ramipril | 0.92 | 0.71–1.20 (two-sided) | 0.5461 | Superiority |
| Telmisartan vs ramipril | 0.88 | 0.68–1.14 | 0.3436 | Superiority |
What the estimate means. An HR of 0.92 corresponds to an 8% lower estimated hazard of the renal composite with the combination.
What the interval says. The two-sided 95% CI of 0.71–1.20 is wide: it is compatible with a 29% lower hazard or a 20% higher hazard. Compared with the cardiovascular composite, the imprecision reflects a smaller population and fewer events. The data are therefore inconclusive about the direction of any effect on this endpoint.
What it does not mean. The point estimate below 1 is not evidence of renal benefit; a result this imprecise does not distinguish benefit from harm.
Why the p-value is not the effect size. P = 0.5461 reflects the combination of a modest point estimate and a wide interval. A larger study with the same HR could produce a much smaller p-value; the p-value summarises compatibility with no effect, not the magnitude of an effect.
Cautions. The registry states that the renal outcomes were not adjudicated, apart from death. Unadjudicated endpoints can carry more measurement noise, which usually biases estimates toward no difference. The composite also includes all-cause mortality, so it combines kidney-specific and non-specific events.
What the estimate means. An HR of 0.88 corresponds to a 12% lower estimated hazard of the renal composite with telmisartan than with ramipril.
What the interval says. The 95% CI of 0.68–1.14 includes 1 and extends from a 32% lower to a 14% higher hazard. Superiority was not demonstrated, and the interval is too wide to support a conclusion of similarity either.
What it does not mean. Although the cardiovascular composite was tested for non-inferiority, this renal comparison was posted as a superiority test. Its non-significance cannot be read as evidence of non-inferiority, because no margin was posted for this endpoint.
Why the p-value is not the effect size. P = 0.3436 simply indicates that data of this kind would not be unusual if there were no true difference.
Cautions. As with the combination, the unadjudicated renal outcomes and the restricted diabetic-nephropathy population limit precision. With three primary endpoints in the programme, each individual test is also subject to multiplicity considerations (Section 12).
9. Primary Results: TRANSCEND
Hazard ratio, telmisartan vs placebo (TRANSCEND)
95% CI: 0.81–1.05 · P = 0.2192
Population: FAS of the TRANSCEND trial · Hypothesis: superiority
What the estimate means. An HR of 0.92 corresponds to an 8% lower estimated hazard of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke or hospitalization for congestive heart failure with telmisartan compared with placebo.
What the interval says. The 95% CI of 0.81–1.05 spans from a 19% lower hazard to a 5% higher hazard. It is wider than the ONTARGET intervals because TRANSCEND was a smaller trial. The interval includes 1, so superiority over placebo on the primary composite was not demonstrated.
What it does not mean. Failing to reject the null hypothesis is not evidence that telmisartan has no effect. The interval leaves open a clinically meaningful reduction as well as a small increase; the trial simply could not distinguish among these possibilities with the precision available.
Why the p-value is not the effect size. P = 0.2192 does not indicate a small effect. It indicates that, given the variability in the data, an HR of 0.92 is not far enough from 1 to be declared statistically significant at the conventional level.
Cautions. TRANSCEND enrolled a distinct population (patients intolerant to ramipril), so its placebo-controlled result cannot be combined directly with the active-controlled ONTARGET comparisons. The two trials answer different questions about different patients.
10. Secondary Endpoint Results
The registry posts Cox regression analyses for many secondary endpoints, each comparing an active arm with ramipril. These analyses are supportive. The registry does not describe a hierarchical testing procedure or a multiplicity adjustment for them, so their p-values should be read as nominal. The ClinicalTrials.gov record also contains further secondary and other analyses beyond those tabulated here.
Cardiovascular components
| Endpoint | Telmisartan + ramipril vs ramipril | Telmisartan vs ramipril |
|---|---|---|
| CV death, non-fatal MI, non-fatal stroke | HR 1.00 (95% CI 0.93–1.09); P = 0.9086 | HR 0.99 (97.5% CI 0.90–1.08); P = 0.0004; non-inferiority, margin 1.13 |
| Cardiovascular death | HR 1.04 (0.93–1.17); P = 0.4535 | HR 1.00 (0.89–1.12); P = 0.9421 |
| Non-fatal myocardial infarction | HR 1.08 (0.94–1.23); P = 0.2909 | HR 1.08 (0.94–1.24); P = 0.2534 |
| Non-fatal stroke | HR 0.92 (0.79–1.06); P = 0.2248 | HR 0.91 (0.79–1.05); P = 0.1829 |
| Hospitalization for congestive heart failure | HR 0.95 (0.82–1.10); P = 0.4984 | HR 1.12 (0.97–1.29); P = 0.1203 |
| Newly diagnosed congestive heart failure | HR 0.94 (0.83–1.07); P = 0.3732 | HR 1.06 (0.94–1.20); P = 0.3633 |
| Cardiovascular revascularization procedure | HR 1.04 (0.97–1.13); P = 0.2713 | HR 1.03 (0.95–1.11); P = 0.5150 |
Intervals are 95% unless stated. The three-component composite (without heart-failure hospitalization) repeats the pattern of the primary endpoint: non-inferiority of telmisartan was tested with the same margin, with an upper 97.5% limit of 1.08, and the combination showed no evidence of superiority. None of the individual components shows a difference whose confidence interval excludes 1. Individual components have fewer events, so their intervals are wider and they are not powered for separate conclusions.
Renal outcomes in diabetic nephropathy (FAS [DN])
| Endpoint | Telmisartan + ramipril vs ramipril | Telmisartan vs ramipril |
|---|---|---|
| Doubling of serum creatinine | HR 1.25 (0.73–2.15, two-sided); P = 0.4221 | HR 0.90 (0.51–1.60); P = 0.7305 |
| Progression to ESRD | HR 0.88 (0.54–1.45); P = 0.6248 | HR 0.62 (0.36–1.05, two-sided); P = 0.0751 |
| All-cause mortality | HR 0.87 (0.63–1.18); P = 0.3682 | HR 0.92 (0.69–1.24); P = 0.6014 |
These components of the renal primary composite have very wide intervals; the upper limit for doubling of serum creatinine with the combination reaches 2.15. Point estimates on either side of 1 carry little information when intervals are this wide. The telmisartan versus ramipril estimate for ESRD (HR 0.62, P = 0.0751) is the kind of result that is easily over-read: the interval reaches 1.05, and it is one of many secondary comparisons.
Renal outcomes in the full ONTARGET population
| Endpoint | Telmisartan + ramipril vs ramipril | Telmisartan vs ramipril |
|---|---|---|
| Doubling of serum creatinine | HR 1.14 (0.91–1.42); P = 0.2550 | HR 1.07 (0.86–1.34); P = 0.5297 |
| Progression to ESRD | HR 1.13 (0.82–1.56); P = 0.4593 | HR 0.95 (0.68–1.32); P = 0.7468 |
| New microalbuminuria | HR 0.88 (0.80–0.97); P = 0.0133 | HR 0.93 (0.84–1.02); P = 0.1251 |
| New macroalbuminuria | HR 0.81 (0.67–0.97); P = 0.0213 | HR 0.90 (0.75–1.07); P = 0.2396 |
| Combined: creatinine doubling, ESRD, new micro- or macroalbuminuria | HR 0.90 (0.83–0.98); P = 0.0111 | HR 0.92 (0.85–1.00); P = 0.0606 |
| Normalisation from micro- or macroalbuminuria to normoalbuminuria | HR 1.19 (1.05–1.35); P = 0.0082 | HR 1.08 (0.95–1.23); P = 0.2164 |
Other secondary endpoints
| Endpoint | Population | Telmisartan + ramipril vs ramipril | Telmisartan vs ramipril |
|---|---|---|---|
| Newly diagnosed diabetes | Patients without diabetes at baseline | HR 0.92 (0.77–1.10); P = 0.3485 | HR 1.14 (0.96–1.36); P = 0.1235 |
| Cognitive decline | Patients with MMSE at baseline | Risk ratio 0.99 (0.89–1.11); chi-squared P = 0.8690 | — |
Newly diagnosed diabetes is analysed only among patients free of diabetes at baseline, as it must be for an incidence endpoint. Cognitive decline is analysed as a binary outcome with a risk ratio: a risk ratio of 0.99 means the proportion of patients with cognitive decline was almost the same in the two groups, and the interval of 0.89–1.11 is compatible only with small differences in either direction.
11. Safety: Serious Adverse Events
The ClinicalTrials.gov record reports the number of participants with at least one serious adverse event and the number at risk in each arm.
| Trial | Arm | Affected | At risk |
|---|---|---|---|
| ONTARGET | Telmisartan + ramipril | 5,268 | 8,502 |
| ONTARGET | Telmisartan | 5,506 | 8,542 |
| ONTARGET | Ramipril | 5,375 | 8,576 |
| TRANSCEND | Telmisartan | 1,781 | 2,954 |
| TRANSCEND | Placebo | 1,830 | 2,972 |
The majority of participants in every arm experienced at least one serious adverse event over the long follow-up, which is expected in an older, high-risk population in which the efficacy outcomes themselves (myocardial infarction, stroke, heart-failure hospitalization) typically qualify as serious events. The registry presents these counts descriptively, without a between-arm statistical test. Because serious adverse events overlap heavily with efficacy events, overall SAE counts are a blunt instrument for comparing tolerability; specific event categories are more informative.
12. Multiplicity and Endpoint Hierarchy
The programme has three registered primary endpoints, two active comparisons within ONTARGET, and a large number of secondary analyses. Each additional test raises the chance that at least one result appears significant by chance alone.
| Analysis | Role | Interpretation |
|---|---|---|
| Telmisartan vs ramipril, CV composite | Primary; non-inferiority | Confirmatory; judged against the 1.13 margin using a 97.5% CI |
| Combination vs ramipril, CV composite | Primary; superiority | Confirmatory; superiority not shown |
| Renal composite in diabetic nephropathy | Primary; superiority | Neither comparison shows a difference; unadjudicated outcomes in a subset |
| TRANSCEND, CV composite | Primary; superiority | Separate population; superiority over placebo not shown |
| Secondary cardiovascular, renal and other endpoints | Secondary | Supportive; nominal p-values; no multiplicity procedure reported in the registry |
The use of a 97.5% interval for the non-inferiority comparison suggests that some form of alpha control across the primary comparisons was built into the design, but the ClinicalTrials.gov record does not describe the procedure. Among the secondary endpoints, several albuminuria outcomes have p-values between 0.0082 and 0.0213. Against the background of dozens of secondary comparisons, results of this size warrant caution unless they were protected within a prespecified hierarchy.
13. Statistical Methods Explained
Why is non-inferiority judged against the margin rather than the p-value?
The question in a non-inferiority test is not whether telmisartan differs from ramipril but whether it is worse by more than a prespecified amount. The decision therefore depends on where the confidence interval lies relative to the margin of 1.13. The upper 97.5% limit of 1.10 is below 1.13, so non-inferiority is shown. The accompanying p-value of 0.0019 is a test against the margin, not against HR = 1; reading it as "telmisartan is significantly different from ramipril" would be the opposite of what the result says.
Why can one trial test non-inferiority and superiority at the same time?
ONTARGET contains two separate contrasts with a common reference arm. Telmisartan alone is an alternative to ramipril, so the relevant question is whether it preserves ramipril's effect (non-inferiority). The combination adds to ramipril, so the relevant question is whether it improves on it (superiority). Each contrast has its own null hypothesis, and the trial's conclusions for one do not transfer to the other.
What does a hazard ratio of 0.99 with a 95% CI of 0.92–1.07 tell us?
It tells us more than "not significant". The interval is narrow enough to rule out, at the 95% level, reductions in hazard larger than 8% and increases larger than 7%. For a large, well-conducted trial, a narrow interval centred on 1 is informative evidence that any effect is small, which is different from a small trial whose interval is wide and centred on 1.
Why was Cox regression used for almost every endpoint?
The endpoints are times to a first event over a 56-month time frame, and patients were followed for different lengths of time. Cox regression uses the timing of each event and handles right-censoring for patients who had not had an event by the end of their follow-up. It gives a single relative measure, the hazard ratio, without assuming a particular shape for the baseline hazard. Kaplan-Meier curves would normally accompany these analyses to show absolute event rates over time; the registry does not report them.
Why is cognitive decline analysed with a chi-squared test and a risk ratio?
Cognitive decline was assessed by comparing Mini Mental State Examination results, which yields a yes/no outcome at assessment rather than a precisely dated event. A risk ratio compares proportions, and the chi-squared test assesses whether those proportions differ more than expected by chance. The risk ratio of 0.99 (95% CI 0.89–1.11) is directly interpretable as the ratio of the proportions of patients with decline.
How should an HR above 1 be read for "normalisation to normoalbuminuria"?
The direction of a hazard ratio always refers to the event being counted. For most endpoints in ONTARGET the event is harmful, so HR < 1 favours the experimental arm. For normalisation the event is beneficial, so the combination's HR of 1.19 (95% CI 1.05–1.35) means a 19% higher estimated rate of returning to normal albumin levels. Reading hazard ratios without checking what event is counted is a common source of error.
14. Limitations
- Non-inferiority depends on the margin: the conclusion for telmisartan holds relative to a margin of 1.13. The registry does not report how the margin was derived, and its clinical adequacy is a judgement outside the statistics.
- Analysis population for non-inferiority: results are posted for the full analysis set. In non-inferiority designs, analyses that include non-adherent patients can bias toward similarity, and a per-protocol analysis is not reported in the registry summary.
- Proportional hazards: each result is a single hazard ratio over 56 months. The registry does not report whether the proportional-hazards assumption was checked, nor does it report Kaplan-Meier curves or absolute event rates by arm.
- Unadjudicated renal outcomes: the renal primary endpoint components other than death were not adjudicated, which can add measurement error.
- Subset analysis for the renal primary endpoint: the diabetic-nephropathy population is a subset of the trial, producing wide confidence intervals.
- Multiplicity: three primary endpoints, two comparisons per ONTARGET endpoint and many secondary analyses are reported, and the registry does not describe a multiplicity strategy for the secondary endpoints.
- Surrogate endpoints: albuminuria outcomes that favour the combination do not correspond to favourable estimates for doubling of creatinine or ESRD.
- Limited adverse-event collection: non-serious adverse events were collected only when they led to discontinuation, so tolerability comparisons are incomplete.
- No stratification or covariate details: the registry does not report stratification factors or model covariates for the Cox analyses.
15. Why This Trial Matters Statistically
ONTARGET is a valuable teaching case because a single, very large programme contains a non-inferiority test, a superiority test against an active control, a placebo-controlled companion trial, a subset-defined primary endpoint and an instructive conflict between surrogate and hard secondary outcomes.
| Concept | How it appears in ONTARGET |
|---|---|
| Non-inferiority design | Telmisartan vs ramipril, margin 1.13 on the hazard-ratio scale |
| Superiority vs active control | Telmisartan + ramipril vs ramipril |
| Placebo-controlled companion trial | TRANSCEND for patients intolerant to ramipril |
| Cox regression | Hazard ratios for all time-to-event endpoints |
| Confidence-interval level | 97.5% intervals for non-inferiority comparisons; 95% elsewhere |
| Composite endpoints | Time to first cardiovascular or renal event |
| Analysis populations | Full analysis sets and baseline-defined subsets |
| Risk ratio and chi-squared test | Binary cognitive-decline outcome |
| Multiplicity | Three primary endpoints and many secondary comparisons |
| Surrogate vs clinical outcomes | Albuminuria results diverge from creatinine doubling and ESRD |
| Informative null result | Narrow CI around HR 0.99 for the combination |
16. Related Tutorials
Learn more about the methods used in this trial:
17. Related Calculators
18. Sources
- ClinicalTrials.gov: NCT00153101 — Effectiveness and Safety of Ramipril Alone Compared With Telmisartan Alone and in Combination With Ramipril in Patients at High Risk for Cardiovascular Events (ONTARGET/TRANSCEND).
- PubMed: PMID 40490702.
- PubMed: PMID 38682786.
- PubMed: PMID 37890035.
- PubMed: PMID 37466151.
- PubMed: PMID 35057807.
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19. Record Summary
ONTARGET shows how much depends on the hypothesis being tested. With virtually the same point estimate near 1, telmisartan alone met its non-inferiority criterion against ramipril (HR 1.01; 97.5% CI 0.93–1.10; margin 1.13), while the combination did not show superiority (HR 0.99; 95% CI 0.92–1.07). The renal primary endpoint in diabetic nephropathy and the TRANSCEND primary endpoint were both inconclusive, with intervals that include 1. The most useful interpretation combines hazard ratios, confidence intervals relative to 1 and to the margin, the analysis population, the distinction between surrogate and clinical outcomes, and the number of comparisons performed.