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