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Brain Trauma Stroke
Table 1: Prevention Regimen for Effectively Avoiding Second
angioedema (2.6 versus 1.7%; p=0.01) compared with those receiving
Strokes Trial 2x2 Factorial Study Design
ramipril. However, this benefit was offset by an increase in hypertensive
symptoms (2.6 versus 1.7%; p<0.001). There was no difference in the rate
ASA + ER-DP Clopidogrel
of syncope between the two groups (0.2%). The combination therapy of
Telmisarten ASA + ER-DP + clopidogrel Clopidogrel + ASA + ER-DP
telmisartan plus ramipril showed no benefit over ramipril or telmisartan
placebo + telmisartan placebo + telmisartan
Telmisarten placebo ASA + ER-DP + clopidogrel Clopidogrel + ASA + ER-DP
monotherapy; rather, combination therapy was associated with an
placebo + telmisartan placebo placebo + telmisartan placebo
increased risk of syncope (0.3 versus 0.2%; p=0.03), hypotensive symptoms
ASA = aspirin; ER-DP = extended-release dipyridamole.
(4.8 versus 1.7%; p<0.001) and renal dysfunction (13.5 versus 10.2%;
The original study design was amended to remove aspirin from the clopidogrel comparator
p<0.001). This phenomenon had previously been observed where the
following the publication of the results of Management of Atherothrombosis with
Clopidogrel in High-risk patients (MATCH) in May 2004, at which point only 2,027 study
combination of the ARB valsartan and the ACE inhibitor captopril led to an
subjects had received a maximum of eight months’ treatment with clopidogrel plus aspirin.
increased incidence of hypotension without demonstrating any additive
effect in reducing the occurrence of the primary outcome.
40
Data from
Antihypertensive Agents ONTARGET therefore offer an alternative to ramipril with decreased risk of
Blood pressure is the strongest risk factor in stroke. With a direct relationship developing angioedema in telmisartan, providing patients and physicians
between blood pressure and the risk of stroke,
29
even minor decreases in with an additional option in preventing vascular events depending on the
blood pressure can reduce the risk of stroke.
30
Current ESO guidelines patient’s inclination to adverse events.
recommend regular monitoring of blood pressure as well as lowering of
blood pressure following stroke.
6
Using an angiotensin-converting enzyme The Rationale and Results of Prevention Regimen for
(ACE) inhibitor and a diuretic has been shown to reduce the rate of Effectively Avoiding Second Strokes Study
recurrent stroke in the Perindopril Protection against Recurrent Stroke Study In May 2008, results from the highly anticipated Prevention Regiment for
(PROGRESS).
31
However, several studies have suggested that a system Effectively avoiding Second Strokes (PRoFESS) study were presented at the
independent of blood pressure lowering may also benefit stroke patients. XVII European Stroke Conference (ESC) in Nice, France. As the largest-ever
The use of ACE-inhibitor therapy (ramipril) in the Heart Outcomes recurrent stroke prevention trial, PRoFESS was a double-blind, placebo-
Prevention Evaluation (HOPE) trial was effective in reducing the rate of controlled trial that took place at 695 sites in 35 countries, with 20,332
stroke in patients with previous cardiovascular events or high-risk diabetes, patients randomised to receive a combination of 200mg extended-release
despite only a small reduction in blood pressure.
32
dipyridamole plus 25mg aspirin twice daily, or 75mg of daily clopidogrel,
while also undergoing simultaneous randomisation to 80mg telmisartan or
The actions of angiotensin II, a major effector of the renin–angiotensin placebo in a 2x2 factorial study design (see Table 1).
41
The original study
system (RAS), can induce vasoconstriction, ultimately resulting in design had a combination of clopidogrel plus aspirin, but aspirin was
increased blood pressure.
33
Angiotensin II has also been implicated in discontinued in the comparator arm shortly after the data from MATCH
organ damage via oxidative, proliferative, inflammatory and fibrotic were made available, and the study continued with clopidogrel
pathways.
34,35
Although ACE inhibitors are effective in lowering blood monotherapy. A test for treatment interaction found that there was no
pressure, humans can generate angiotensin II independently of ACE interaction between the antiplatelet and telmisartan arms (p=0.35).
42
inhibition, such that not all angiotensin II is blocked. In these terms, it is Patients 55 years of age or older who experienced an ischaemic stroke
logical to block the action of angiotensin II at its receptor. Indeed, while within 90 days prior to randomisation were eligible to participate in the
some angiotensin II receptor blockers (ARBs) can reduce blood pressure study. The criteria were revised after the enrolment of approximately 6,000
as well as cardiovascular events,
36
studies have also shown that ARBs are patients to allow for the inclusion of younger patients from 50 to 54 years
able to reduce the frequency of recurrent stroke.
37,38
of age, and patients with less recent strokes ranging from 90 to 120 days
if at least two other risk factors were present. Patients were excluded if they
ACE inhibitors have proved highly beneficial in reducing mortality, had experienced a primary haemorrhagic stroke or severe disability
myocardial infarction, stroke and heart failure in high-risk patients with stemming from the qualifying stroke, if they were contraindicated to any
heart failure, left ventricular dysfunction, prior vascular diseases or diabetes, of the antiplatelets in the study or if they possessed any other factors that
but these drugs also increase the rates of cough and angioedema as a result would make them unsuitable for randomisation.
41
This trial randomised
of reduced bradykinin degradation and enhanced vasodilation. The patients extremely early at a median of 15 days; nearly 40% of all patients
Ongoing Telmisartan Alone and in combination with Ramipril Global were randomised within 10 days of stroke.
42
Patients were followed up for
Endpoint Trial (ONTARGET) was the first study to compare ARBs versus ACE a mean duration of 2.5 years; 1,495 patients (7.4%) died during the study,
inhibitors. This trial evaluated how an alternative agent such as the ARB and 125 patients (0.6%) were lost to follow-up (see Figure 1). PRoFESS was
telmisartan would compare with the ACE inhibitor ramipril in terms of safety a truly novel study; prior to PRoFESS there had been no direct head-to-head
and efficacy in preventing cardiovascular events, and tested whether the comparisons between the available antiplatelet options, nor had there
combination of an ACE and ARB together would be superior to either drug been any information available as to the safety and efficacy of
alone.
39
Patients with vascular disease or high-risk diabetes were antithrombotic therapy in combination with additional RAS inhibition. The
randomised to receive ramipril (10mg/day; n=8,576), telmisartan study also endeavoured to assess the effects of these treatments on
(80mg/day; n=8,542) or a combination of the two drugs (n=8,502), and cognition and disability.
were followed up for a median of 56 months. Telmisartan demonstrated
statistical non-inferiority compared with ramipril in reducing the composite PRoFESS was the first trial to directly compare the safety and efficacy of two
outcome of death from cardiovascular causes, myocardial infarction, stroke different antiplatelet agents following non-cardioembolic stroke. While the
or hospitalisation. Furthermore, patients treated with telmisartan had pre-specified criteria for non-inferiority were not met in the comparison of
significantly lower rates of cough (1.1 versus 4.2%; p<0.001) and aspirin plus extended-release dipyridamole versus the active comparator
52 EUROPEAN NEUROLOGICAL REVIEW
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