Clinical Trials,Epidemiologic studies, Registries are good but not perfect.

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Clinical Trials,Epidemiologic studies, Registries
are good but not perfect. They do no explain all
the clinical outcomes i.e. the outliers. Thus
there is a great deal to learn from these
outliers as well as unusual clinical cases
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Clinical Trials

• Mean Values do not relfect the outliers in
  clinical trials

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Clinical Trials(and Meta-analyses)

• Restricted enrollment
• Inhomogeneity of the population
• Standardized care may vary
• Treatment Duration varies
• Response to therapy variable
• Pathoanatomy e.g. ventricular function affects
  prognosis
• Snapshot estimation of prognosis not good enough
• Clinical trial results can be misinterpreted
• Adverse events occur in Placebo as well as the
  treatment arm

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Clinical trials

• Factors to consider in Patient specific treatment
  and prognosis
• Age, gender, diabetes, hypertension,hyperlipidemia
  , Stroke
• Persistant symptoms or extensive ischemia
• Poor exercise performance
• Life threatening arrhyhmias
• Degree of LV impairment
• Location and severity of coronary stenoses
• Presence of absence of spasm
• Psycho-social factors

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Patient Specific Treatment and Prognosis

• May require combinations of
• Multiple imaging modalities
• ECG, Echo, CTA, MRA
• Biomarkers
• Usual and some not so usual,e.g Uric Acid
• Genotype
• Combined with biologic, cultural, social and
  environmental factors

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ONTARGET
Trial design Patients at high risk for
cardiovascular events, but without heart failure,
were randomized to telmisartan, ramipril, or the
combination. Patients were followed for a median
of 56 months.
Results

• Telmisartan (16.7) noninferior combination
  (16.3) not superior to ramipril (16.5) for
  primary endpoint (CV death, MI, stroke, heart
  failure)
• Greater incidence of hypotension in combination
  (4.8) and telmisartan (2.7) groups, compared
  with ramipril group (1.7) (p lt 0.001)
• Less angioedema/cough with telmisartan compared
  with ramipril

16.7
16.3
16.5
11.6
12.5
11.8
15
20

10
10

5
0
0
Conclusions
Primary endpoint
Mortality
CV death, MI, Stroke, Heart Failure

• Telmisartan or ramipril can be used alternatively
  in hypertensive patients at high risk for
  cardiovascular events

Telmisartan (n 8,542)
Combination (n 8,502)
Ramipril (n 8,576)



Telmisartan vs. ramipril for noninferiority
The ONTARGET investigators. N Engl J Med
20083581547-59
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Who should be ONTARGET

• The ONgoing Telmisartan Alone and in combination
  with Ramipril Global Endpoint Trial (ONTARGET)
  unequivocally demonstrated that telmisartan is
  effective for the prevention of cardiovascular
  events in a high-risk population.

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Who should be ONTARGET

• Patients at high risk
• coronary artery disease,
• peripheral arterial occlusive disease,
• stroke or recent transient ischaemic attack,
• diabetes with end-organ damage.

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Who should be ONTARGET

• Prevalence of these High Risk Patients
• In the US alone, it is estimated that 28 million
  patients have risk factors similar to those of
  the patients in ONTARGET

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Who should be ONTARGET

• Challenge
• The challenge now is
• to translate ONTARGET into clinical practice and,
• specifically, to assess the relative place(s) of
  telmisartan (and ramipril) in the management of
  high-risk patients

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Who should be ONTARGET

• A common scenario
• Telmisartan may be preferred for patients with
  hypertension and cardiovascular disease,
  especially those who are intolerant of
  angiotensin-converting enzyme (ACE) inhibitors.

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Who should be ONTARGET

• The role of telmisartan in patients will depend
  on their clinical history.
• As telmisartan offers superior 24-hour blood
  pressure control compared with ramipril, should
  it be the preferred treatment option for ALL
  patients with hypertension?

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Who should be ONTARGET

• A common scenario in which telmisartan may be
  preferred
• High-risk hypertensive patients, who do not reach
  BP goal with ACEIs
• These patients could be switched directly to
  Telmisartan

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Who should be ONTARGET

• In the patients who have ACEI intolerance
• because of either cough or allergy,
• Telmisartan would be the obvious choice

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Who should be ONTARGET

• Summary
• Telmisartan is clinically useful
• in patients with hypertension, cardiovascular
  disease and diabetes in both genders

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Who should be ONTARGET

• A Clinician Looking at the Data
• Reviewing the prespecified subgroup analysis of
  telmisartan vs. ramipril, there were some trends
  but nothing statistically significant
• However, these data are average data for the
  group studied. Several individual patients i.e.
  Outliers may have benefitted from either and ACEI
  or an ARB

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The message to convey is that the similar
results between telmisartan and ramipril were
consistent in all subgroups
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Who should be ONTARGET

• Some of the concerns that need to be considered
  by the practitioner are
• Using either drug in patients with severe
• chronic kidney disease
• acute renal failure,
• Be aware and monitor for
• hyperkalemia,
• hypotension,
• syncope.

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Who should be ONTARGET

• The combination of telmisartan and ramipril may
  be better for patients with severe hypertension,
  
• However telmisartan or ramipril alone seems to be
  sufficient for cardiovascular protection

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Who should NOT be ONTARGET

• Clinical conditions not tested in ONTARGET
  include
• Symptomatic heart failure
• Other CV diseases
• i.e. significant valve stenosis, hypertrophic
  cardiomyopathy, poorly functioning prosthetic
  valves, constrictive pericarditis, complex
  congenital heart disease, planned cardiac surgery
  or angioplasty within three months, heart
  transplant recipients, syncope of unknown
  etiology less than three months

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Who should NOT be ONTARGET

• Clinical conditions not tested in ONTARGET
  include
• uncontrolled hypertension greater than 160/100
  mmHg
• strokes due to intracerebral haemorrhage
• significant renal disease
• renal artery stenosis, creatinine clearances less
  than 0.6 mL/min or creatinine greater than 3
  mg/dL, hyperkalemia (potassium greater than 5.5
  mmol/L), proteinuria
• hepatic dysfunction
• primary aldosteronism

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Who should be ONTARGET

• No data exist that allow the clinician to apply
  the results of ONTARGET to these types of
  patients.

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Who Should Be ONTARGET?

• The message for the practitioner
• High risk patients with cardiovascular disease or
  diabetes can be treated with telmisartan 80mg, as
  it is as effective as ramipril 10mg but better
  tolerated
• Thus either drug can be used based on patient and
  physician preferences.
• But Must use doses studied in patients at high
  risk for cardiovascular events

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Who Should Be ONTARGET?

• The message for the practitioner
• There is no evidence for using a combination of
  the two drugs in the doses used in the Trial and
  there are no data for using a combination low
  dose of Telmisartan or Ramipril