Telmisartan Randomised Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease - TRANSCEND

Description:

The goal of this trial was to assess whether the long-term use of telmisartan, an angiotensin-receptor blocker (ARB), is associated with a reduction in cardiovascular endpoints in patients with cardiovascular disease or high-risk diabetes and without heart failure, who are intolerant to angiotensin-converting enzyme (ACE) inhibitors, when compared with placebo, in addition to usual therapies.

Hypothesis:

Telmisartan would be associated with a reduction in cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure in patients with cardiovascular disease or high-risk diabetes and without heart failure, when compared with placebo.

Study Design

Study Design:

Patients Screened: 6,666
Patients Enrolled: 5,926
Mean Follow Up: 56 months (median)
Mean Patient Age: 66.9 years
Female: 43

Patient Populations:

  • Intolerance to ACE inhibitors, with a specifically documented cause
  • Established coronary artery, cerebrovascular, or peripheral vascular disease
  • Diabetes with evidence of end-organ damage

Exclusions:

  • Need for or inability to discontinue ARBs
  • Known hypersensitivity or intolerance to ARBs
  • Known heart failure
  • Significant primary valvular or cardiac outflow tract obstruction
  • Constrictive pericarditis
  • Complex congenital heart disease
  • Unexplained syncope
  • Planned cardiac surgery or cardiac revascularization within the previous 3 months
  • Systolic blood pressure over 160 mm Hg
  • Heart transplantation
  • Subarachnoid hemorrhage
  • Significant renal artery stenosis
  • Creatinine levels >3.0 mg/dl
  • Proteinuria
  • Hepatic dysfunction

Primary Endpoints:

Composite of cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure

Secondary Endpoints:

  • Composite outcome of cardiovascular death, myocardial infarction, or stroke
  • New congestive heart failure
  • New diabetes
  • Atrial fibrillation
  • Cognitive decline or dementia
  • Nephropathy
  • Revascularization

Drug/Procedures Used:

Telmisartan 80 mg daily or matching placebo

Concomitant Medications:

Aspirin (74.7%), beta-blockers (58.3%), statins (55.2%), and diuretic (33%)

Principal Findings:

After a 1-month run-in phase, 5,926 patients were randomized, 2,954 to telmisartan and 2,972 to placebo. The majority of the patients (61.1%) were European, whereas 21.3% were Asian; only 1.8% were African in origin. The major reason for discontinuation of ACE inhibitors in these patients was cough (88.2%), whereas angioedema or anaphylaxis was noted in 1.3% of the patients. About 76.4% of the patients had hypertension, 74.6% had coronary artery disease, 22% had a history of stroke or transient ischemic attack, and 35.7% had diabetes. By the end of the study, a small proportion of the patients were on ARBs other than telmisartan (6.7%). As expected, a greater proportion of patients in the placebo arm were given nonstudy blood pressure–lowering medications over the course of the study, whereas the use of statins and antiplatelet agents was similar.

The mean blood pressure was lower in the telmisartan group at all time points studied, including at the end of the study (3.2/1.3 mm Hg). The primary endpoint of cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure was similar between the ARB and placebo arms (15.7% vs. 17.0%, hazard ratio [HR] 0.92, 95% confidence interval [CI] 0.81-1.05, p = 0.22). The incidence of cardiovascular death, myocardial infarction, or stroke was lower in the telmisartan group (13.0% vs. 14.8%, HR 0.87, 95% CI 0.76-1.0, p = 0.048). The separation of the survival curves was apparent only after about 1.5 years or so. The reduction in this composite endpoint was driven primarily by a reduction in the incidence of myocardial infarction (3.9% vs. 5.0%, p = 0.06), whereas the incidence of cardiovascular death, stroke, and heart failure seemed to be fairly similar.

Of the secondary outcomes, there was a slight reduction in the incidence of new diabetes mellitus (11.0% vs. 12.8%, p = 0.08), left ventricular hypertrophy (5.0% vs. 7.9%, p < 0.001), and any cardiovascular hospitalization (30.3% vs. 33%, p = 0.025). There was no difference in the incidence of all-cause mortality (12.3% vs. 11.7%, p = 0.49). No difference was also noted in the incidence of a composite renal outcome (dialysis, doubling of serum creatinine, changes in estimated GFR, or changes in albuminuria) (1.96% vs. 1.55%, p = 0.20).

The total number of study drug discontinuations was similar between the two arms (36.9% vs. 38.5%, p = 0.22), although there was a near doubling of discontinuations in the telmisartan arm due to renal abnormalities (0.8% vs. 0.4%, p = 0.07) and symptomatic hypotension (1% vs. 0.5%, p = 0.05), whereas the incidence of angioedema was similar (0.1%).

Interpretation:

The results of the large, multicenter TRANSCEND study demonstrate that in patients who are intolerant to ACE inhibitors, telmisartan is not associated with a significant reduction in the incidence of cardiovascular death, myocardial infarction, stroke, hospitalization for heart failure, or renal outcomes, when compared with placebo, although the composite endpoint of cardiovascular death, myocardial infarction, or stroke (used by the same investigators in the HOPE trial) was lower in the telmisartan group, compared with placebo, primarily driven by a reduction in the incidence of myocardial infarction.

Subanalysis seemed to indicate that the benefit was noted only after the first 6-12 months of treatment had elapsed. Adherence to telmisartan was high in these patients, including those who had angioedema or anaphylaxis with ACE inhibitors, suggesting that ARBs could potentially be safely used in high-risk patients who have an indication for angiotensin blockade, but are intolerant to ACE inhibitors.

One question that arises is that both ACE inhibitors (HOPE, PEACE trials) and specific ARBs (candesartan [CHARM] and valsartan [ValHeFT] trials), have been shown to reduce hospitalization for heart failure in patients with left ventricular dysfunction. However, the results of TRANSCEND and the recently published PRoFESS trial seem to suggest that telmisartan may be less efficacious than these agents in reducing this outcome. This is, however, contradicted by the recently published ONTARGET study, which demonstrated noninferiority between telmisartan and ramipril in high-risk patients for this outcome. Further studies are needed to clarify the role of telmisartan in patients with heart failure.

At the present time, ACE inhibitors seem to be the most appropriate first-line agents for patients needing renin-angiotensin-system blockade. Telmisartan may be a reasonable alternative in patients who are intolerant to ACE inhibitors.

References:

Mann JF, Schmieder RE, Dyal L, et al. Effect of telmisartan on renal outcomes: a randomized trial. Ann Intern Med 2009;151:1-10.

The TRANSCEND Investigators. Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial. Lancet 2008;372:1174-83.

The TRANSCEND Study: A Randomized Placebo-Controlled Clinical Trial Evaluating the Effects of Telmisartan in High Risk Individuals Without Heart Failure. Presented by Dr. Salim Yusuf at the European Society of Cardiology Congress, Munich, Germany, August/September 2008.

Clinical Topics: Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Lipid Metabolism, Novel Agents, Acute Heart Failure, Hypertension

Keywords: Hypertrophy, Left Ventricular, Coronary Artery Disease, Ischemic Attack, Transient, Platelet Aggregation Inhibitors, Renin, Hypotension, Creatinine, Benzoates, Renal Dialysis, Benzimidazoles, Research Personnel, Confidence Intervals, Cough, Hypertension, Myocardial Infarction, Stroke, Valine, Ramipril, Tetrazoles, Peripheral Vascular Diseases, Heart Failure, Ventricular Dysfunction, Left, Diabetes Mellitus


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