ONTARGET

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Yusuf S, et al. "Telmisartan, ramipril, or both in patients at high risk for vascular events". The New England Journal of Medicine. 2008. 358(15):1547-1559.
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Clinical Question

In patients with cardiovascular disease or diabetes mellitus with complications, is telmisartan non-inferior to ramipril, and is the combination of both drugs superior to ramipril alone for the composite endpoint of death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for heart failure.

Bottom Line

In patients with cardiovascular disease or DM with complications, telmisartan is at least as good as ramipril in preventing death, MI, and stroke, and the combination of telmisartan plus ramipril had no increase in benefit but was associated with more adverse effects.

Major Points

The efficacy of ACE inhibitors in patients with CV disease and stroke has been demonstrated in multiple trials including SOLVD (1991, HF), SAVE (1992, post-MI), HOPE (2000, high-CV risk), and EUROPA (2003, stable CAD)[1] Of these, HOPE studied the most heterogeneous population. As inhibition of angiotensinogen II may be incomplete, ARBs may provide an additional benefit through further blockade of the RAAS system to counter this "escape phenomenon."[2] No large RCT had been performed demonstrating efficacy of ARBs against or with ACE inhibitors for individuals at high risk for CV disease.

The 2008 Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) randomized 25,620 mostly male patients with CAD, PAD, cerebrovascualr disease, or DM with end-organ damage to ramipril, telmesartan, or a combination of both. With a median follow-up of 56 months, there was no difference in the rate of the primary outcome of CV mortality, MI, stroke, or HF hospitalization (16.5% vs. 16.7% vs. 16.3%, respectively). Telmisartan was non-inferior to ramipril. Futhermore, there was no difference in any of the components of the primary outcome or other predefined analyses except for increase rate of nephropathy in the combination group (10.2% vs. 10.6% vs. 13.5%; NNH for comibination vs. ramipril 30), which led to a higher rate of discontinuation in the combination group than the other two groups. Ramipril was discontinued more frequently than telmesartan, which was driven by higher rates of cough and angioedema. Telmesartan had higher discontinuation because of symptoms concerning for hypotension. Discontinuation was highest in the combination group than the other two gruops because of poor tolerance of the therapy from increased rates of symptomatic hypotension, syncope, cough, diarrhea, and renal impairment.

The lack of benefit of dual ACE inhibitor/ARB therapy is similar to the findings in VALIANT in post-MI patients with LV dysfunction. A benefit was found in patients with HFrEF in CHARM-Added and Val-HeFT.

A surprising finding of this trial was the discordance between blood pressure and outcomes. The combination group achieved about a 2-3 mmHg reduction in SBP though did not have benefit in any outcomes measured. This lower blood pressure likely contributed to the degree of renal dysfunction, syncope, and hypotensive symptoms. Whether the statistically insignificant trend towards increased non-CV mortality in the combination group is of clinical significance is unclear.

Guidelines

JNC 8 hypertension guidelines (2014, adapted)[3]

  • General population, age <60 years - Start pharmacologic therapy if:
    • SBP ≥140 mmHg for goal SBP <140 mmHg (expert opinion, grade E)
    • DBP ≥90 mmHg for goal DBP <90 mmHg (strong recommendation, grade A for ages 30-59; expert opinion, grade E for ages 18-29 years)
  • General population, age ≥60 years - Start pharmacologic therapy if:
    • SBP ≥150 mmHg for goal SBP <150 mmHg (strong recommendation, grade A)
      • Continue any well-tolerated SBP treatments for goal SBP <140 mmHg without modifications (expert opinion, grade E)
    • DBP ≥90 mmHg for goal DBP <90 mmHg (strong recommendation, grade A)
  • CKD, age ≥18 years
    • Start pharmacologic therapy if SBP or DBP is ≥140 or 90 mmHg, respectively for goal <140/90 (expert opinion, grade E)
    • Regardless of race of diabetic status, initial or add-on therapy as ACE-inhibitor or ARB to improve outcomes of kidney disease (moderate recommendation, grade B)
  • DM, age ≥18 years - Start pharmacologic therapy if SBP or DBP is ≥140 or 90 mmHg, respectively for goal <140/90 (expert opinion, grade E)
  • General non-black population including DM - Initial therapy with a thiazide, CCB, ACE-inhibitor, or ARB (moderate recommendation, grade B)
  • General black population including DM - Intial therapy with a thiazide or CCB (moderate recommendation, grade B for general black population; weak recommendation, grade C for black population with DM)
  • Treatment goals (expert opinion, grade E)
    • If refractory BP at the end of one month, increase dose of monotherapy or add second agent (thiazide, CCB, ACE-inhibitor, or ARB)
    • If refractory BP on two medications, add third agent (thiazide, CCB, ACE-inhibitor, or ARB)
    • If goal not reached with three drugs then other classes can be used
    • Do not use ACE-inhibitors and ARBs together
    • Consider referral to hypertension specialist if refractory hypertension

Design

  • Multi-centered, double-blind, non-inferiority, randomized control trial
  • N=25,620
    • Ramipril (n=8,576)
    • Telmisartan (n=8,542)
    • Combination (n=8,502)
  • Setting: 733 centers in 40 countries
  • Enrollment: 2001-2003
  • Median follow-up: 56 months
  • Analysis: Intention-to-treat
  • Primary outcome: CV mortality, MI, stroke, or HF hospitalization

Population

Inclusion Criteria

  • Age ≥55 with any of the following:
    • Coronary artery disease - Defined by any of the following:
      • Prior MI, >2 days post uncomplicated MI
      • Stable/unstable angina >30 days with documented multivessel CAD
      • Multivessel PCA >30 days
      • Multivessel CABG surgery >4 years or recurrent angina after surgery
    • Peripheral artery disease - Defined by any of the following:
      • Limb bypass surgery or angioplasty
      • Limb or foot amputation
      • Intermittent claudication with ABI <0.80 on ≥1 side
      • Significant peripheral artery stenosis (>50%) documented by angiography or non-invasive testing
    • Cerebrovascular disease - Defined by any of the following:
      • Prior stroke
      • TIA >7 days and <1 year
    • High-risk diabetes - Defined by evidence of end-organ damage

Exclusion Criteria

  • Inability to discontinue ACE inhibitors or ARBs
  • Hypersensitivity/intolerance to ACE inhibitors or ARBs
  • HF
  • Hemodynamically significant valvular or outflow tract obstruction
  • Constrictive pericarditis
  • Complex congenital heart disease
  • Syncopal episodes of unknown etiology <3 months
  • Planned cardiac surgery/PCA in next 3 months
  • Uncontrolled HTN on therapy defined by BP >160/100 mmHg
  • Heart transplant
  • Subarachnoid hemorrhage-related stroke
  • Significant renal artery disease
  • Liver disease
  • Uncorrected volume or sodium depletion
  • Primary hyperaldosteronism
  • Hereditary fructose intolerance
  • Life- or participation-limiting non-cardiac illnesses
  • Use of another experimental drug
  • Unable to provide written informed consent

Baseline Characteristics

From the ramipril group. Groups were similar.

  • Demographics: Age 66.4 years, female 27.2%
    • Ethnicity: Asian 13.8%, Arab 1.2%, African 2.4%, European 73.1%, Native/Aboriginal 8.7%, other 0.7%
  • PMH: DM 37%, HTN 69%, CAD 74%, MI 48%, stroke/TIA 21%, PAD 13%, LVH 13%, microalbuminuria 13%, smoker 12% (former 52%)
    • Angina:
      • Stable: 35%
      • Unstable: 15%
  • PSH: CABG 22%, PCI 29%
  • Baseline health data: BP 141/82 mmHg, HR 68 bpm, BMI 28 m/kg2
  • Laboratory: Tchol 4.9 mmol/L, LDL 2.9 mmol/L, HDL 1.3 mmol/L, Triglycerides 1.7 mmol/L, glucose 6.7 mmol/L, creatinine 93 umol/L, potassium 4.4 mmol/L
  • Medications: Statin 61%, Beta-Blocker 56%, antiplatelet 80% (ASA 75%, clopidogrel or ticlopidine 11%), diuretic 29%, CCB 33%

Interventions

  • Single-blind run-in period (11.7% excluded before randomization):
    • Ramipril 2.5mg once daily x3 days
    • Ramipril 2.5mg + Telmisartan 40mg daily x7 days
    • Ramipril 5mg + Telmisartan 40mg for 11-18 days
  • Randomization to a group:
    • Ramipril - Ramipril 5 mg PO qday for two weeks then 10 mg PO qday
    • Telmisartan - Telmisartan 80 mg PO qday
    • Combination - Ramipirl 5 mg PO qday for two weeks then 10 mg PO qday + stable dose of telmisartan 80 mg PO qday

Outcomes

Presented as ramipril vs. telmisartan vs. combination (telmisartan vs. ramipril | combination vs. ramipril), unless otherwise noted. RR is risk ratio. For the primary outcome, individuals could have multiple events.

Primary Outcome

Components of the primary outcome are included here for ease of reading.

CV mortality, MI, stroke, or HF hospitalization
16.5% vs. 16.7% vs. 16.3% (RR 1.01; 95% CI 0.94-1.09 | RR 0.99; 95% CI 0.92?1.07)
Telmisartan noninferior to ramipril (P=0.004 in text and P=0.003 in Figure 2)
# of events: 2058 (24.0%) vs. 2042 (23.9%) vs. 2000 (23.5%) (P=0.83 | P=0.38)
CV mortality: 7.0% vs. 7.0% vs. 7.3% (RR 1.00; 95% CI 0.89?1.12 | RR 1.04; 95% CI 0.93?1.17)
MI: 4.8% vs. 5.2% vs. 5.2% (RR 1.07; 95% CI 0.94?1.22 | RR 1.08; 95% CI 0.94?1.23
Stroke: 4.7% vs. 4.3% vs. 4.4% (RR 0.91; 95% CI 0.79?1.05 | RR 0.93; 95% CI 0.81?1.07)
HF hospitalizations: 4.1% vs. 4.6% vs. 3.9% (RR 1.12; 95% CI 0.97?1.29 | RR 0.95; 95% CI 0.82?1.10)

Secondary Outcomes

CV mortality, MI, or stroke
The primary outcome of HOPE and identified as the "main secondary outcome."
Telmisartan non-inferior to ramipril (P=0.001)
14.1% vs. 13.9% vs. 14.1% (RR 0.99; 95% CI 0.91-1.07 | RR 1.00; 95% CI 0.93-1.09)
New HF
6.0% vs. 6.3% vs. 5.6% (RR 1.05; 95% CI 0.93-1.19 | RR 0.94; 95% CI 0.83-1.07)
New diabetes
Included 5,427, 5,294, and 5,280 participants.
6.7% vs. 7.5% vs. 6.1% (RR 1.12; 95% CI 0.97-1.29| RR 0.91; 95% CI 0.78-1.06)
New AF
Included 8,296, 8,259, and 8,218 participants.
6.9% vs. 6.7% vs. 6.5% (RR 0.97; 95% CI 0.86-1.09 | RR 0.96; 95% CI 0.85-1.07)
Dementia or cognitive decline
Not presented
Renal impairment (based on Clinician's judgement)
10.2% vs. 10.6% vs. 13.5% (RR 1.04; 95% CI 0.96-1.14 | RR 1.33; 95% CI 1.22-1.44; P<0.001; NNH 30)
Requiring HD: 0.6% vs. 0.6% vs. 0.8% (RR 1.09; 95% CI 0.74-1.61 | RR 1.37; 95% CI 0.94-1.98)
Revascularization
14.8% vs. 15.1% vs. 15.3% (RR 1.03; 95% CI 0.95-1.11 | RR 1.04; 95% CI 0.97-1.13)

Additional Analyses

All-cause mortality
11.8% vs. 11.6% vs. 12.5% (RR 0.98; 95% CI 0.90-1.07 | RR 1.07; 95% CI 0.98-1.16)
Non-CV mortality
4.8% vs. 4.6% vs. 5.2% (RR 0.96; 95% CI 0.83?1.10 | RR 1.10; 95% CI 0.96?1.26)
Angina
New or worsening: 6.6% vs. 6.3% vs. 6.3% (RR 0.95; 95% CI 0.84?1.07 | RR 0.96; 95% CI 0.85?1.08)
Related hospitalization: 10.8% vs. 11.2% vs. 11.2% (RR 1.04; 95% CI 0.95?1.14 | RR 1.04; 95% CI 0.95?1.14)
TIA
Not presented
Development of LVH
Not presented
Microvascular complications in DM
Not presented
BP changes or ankle-to-arm ratio BP change
Not presented
New malignancies
Not presented
SBP
2-3 mmHg lower in combination group than ramipril

Subgroup Analysis

There was no significant difference in the primary outcome when analyzed by history of CVD, history of DM, enrollment SBP, HOPE risk score, age, or sex.

Adverse Events Leading to Discontinuation

Any medication discontinuation
Participants could be counted more than once if they restarted and discontinued the intervention.
24.5% vs. 23.0% vs. 29.3% (RR 0.94; P=0.02 | RR 1.20; P<0.001)
Permanent discontinuation
Symptoms of hypotension: 1.7% vs. 2.7% vs. 4.8% (RR 1.54; P<0.001 | RR 2.75; P<0.001)
Syncope: 0.2% vs. 0.2% vs. 0.3% (RR 1.27; P=0.49 | RR 1.95; P=0.03
Cough: 4.2% vs. 1.1% vs. 4.6% (RR 0.26; P<0.001 | RR 1.10; P=0.19)
Diarrhea: 0.1% vs. 0.2% vs. 0.5% (RR 1.59; P=0.20 | 3.28; P<0.001)
Angioedema: 0.3% vs. 0.1% vs. 0.2% (RR 0.4; P=0.01 | RR 0.73; P=0.30)
Renal impairment: 0.7% vs. 0.8% vs. 1.1% (RR 1.14; P=0.46 | RR 1.58; P<0.001)

Criticisms

  • No uptitration of telmisartan dose like ramipril may have worsened rates of hypotension in these groups
  • Boehringer Ingelheim was involved with the Operations Committee
  • Writing committee included employees of Boehringer Ingelheim (and Ingelheim Germany)
  • Compared to earlier trials like HOPE and EUROPA, these patients had higher rates of medication optimization for secondary prevention, which may have owed to the small apparent effect
  • Incomplete reporting of causes of death[4]
  • Unclear clinical significance of symptoms of hypotension without correlating blood pressure readings[4]

Funding

  • Boehringer Ingelheim, the makers of Micardis (brand name of telmisartan)
  • The Heart and Stroke Foundation of Ontario
  • Canadian Institutes of Health Research
  • Authors with multiple financial disclosures

Further Reading

  1. Fox KM, et al. "Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: Randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study)." The Lancet. 2003;362(9386):782-788.
  2. Roig E. "Clinical implications of increased plasma angiotensin II despite ACE inhibitor therapy in patients with congestive heart failure." European Heart Journal. 2000;21(1):53-57.
  3. James PA, et al. "2014 evidence-based guideline for the management of high blood pressure in adults: Report from the panel members appointed to the eighth joint national committee (JNC 8)." JAMA. 2014;311(5):507-20
  4. 4.0 4.1 Multiple authors. "Correspondence: Telmisartan, ramipril, or both in patients at high risk of vascular events." The New England Journal of Medicine. 2008; 359(4):426-427.