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THE USE OF ANTI-THROMBOTIC AGENTS IN CEREBRO-VASCULAR AND CARDIO-VASCULAR DISEASE
It is a remarkable reflection that when I was a medical student in the 1970’s, we literally watched many people have heart attacks and strokes and could do nothing about the episode, let alone try and prevent subsequent decline from further events. Six weeks of total bed rest after a heart attack was de rigueur and the major consultant decision during that time was when an individual could be allowed to walk round the bed. During this time, I was fortunate enough to be in the operating theatres at the London Hospital where one of the first coronary angiograms in the UK took place. The procedure took something like four hours and there must have been at least twenty personnel involved, meaning that as a medical student you did not know what was going on.
The cardiologists have been much more aggressive than the neurologists in preventing and treating ‘heart attack’ as opposed to ‘brain attack’.
Various interventions from the moment of an ‘attack’ alters morbidity and mortality and we are slowly chipping away at the knowledge base in order to improve outcomes.
The understanding of the use of anti-thrombotic agents has contributed particularly to the secondary prevention of heart disease and stroke.
The term anti-thrombotic agents, refers to both anti-coagulation with both warfarin or heparin and the use of anti-platelet aggregation agents such as aspirin, dipyridamole and clopidogrel.
Atherosclerosis is now regarded as an inflammatory disease. The fatty streak will lead to atheroma and subsequent to that a complex plaque will form covered by a fibrous cap. When the plaque ruptures thrombosis will occur and death of tissue follow. The thrombosis occurs with plaque rupture because the subendothelial surface is pro-coagulant and this triggers the coagulation activation platelet cascade. It is proposed that complex immune mechanisms are involved in this process but it is being postulated that the process itself is triggered by low-density lipo-protein (LDL).
Although it is perceived that LDL is important in this mechanism, a recent publication in the American Heart Journal showed that in a study involving 140,000 people, there was no difference effectively in individuals presenting with a heart attack and their actual level of LDL. This has led to a concept that it is the inflammatory process that is important rather than the LDL cholesterol. This has clearly altered our thinking about the mechanism by which the statins have such benefit and although they do lower total cholesterol and LDL they also have an impact on the high sensitivity c-reactive protein (HS-CRP) which means that they are probably also having an impact on the inflammation within the arterial wall.
Atrial fibrillation reflects an irregularly irregular beating heart with low flow or even relative stasis within the left atrium. There is also activation of the coagulation pathway and thrombosis is the outcome. This is likened to the situation when blood clots on the venous side of the circulation. It is known that when stroke has occurred in atrial fibrillation that the thrombo-embolic process carries with it a very high risk of further neuro-vascular events. Because the mechanism is akin to venous thrombosis then anti-coagulation with heparin and then warfarin or by warfarin alone is absolutely indicated. This gives a greater than 60% protection from further events.
A recent study, the so-called Active A trial (atrial fibrillation clopidogrel trial with irbesartan for prevention of vascular events – aspirin) examined the role of aspirin plus clopidogrel versus aspirin alone in patients with atrial fibrillation in whom vitamin K antagonists were considered unsuitable because of a high risk of haemorrhage.
This trial demonstrated that the combination of aspirin and clopidogrel reduced the risk of major vascular events compared with aspirin alone.
The study did show a greater risk of haemorrhage with the combination but that risk was considered reasonable given that it was usually gastric bleeding as opposed to further stroke.
The IST trial (international stroke trial) also showed a risk of bleeding when two anti-thrombotic drugs were combined compared to one. In this trial it was a combination of unfractionated heparin and aspirin.
In the MATCH trial (management of atheroma thrombosis with clopidogrel in high risk patients with recent transient ischaemic attack or ischaemic stroke) it was a combination of clopidogrel and aspirin and in the SPORTIF trial (stroke prevention using oral thrombin inhibit in atrial fibrillation) looked at warfarin and aspirin. Even in the PROFESS trial (prevention regimen for effectively avoiding second strokes) there were more intracranial bleeds using dipyridamole and aspirin than with clopidogrel alone after a stroke or transient ischaemic attack.
It would seem that the difference between venous or atrial thrombosis as opposed to arterial thrombosis is the activation of the platelet cascade.
In order to prevent arterial vascular events then treatment that blocks the platelet activation pathway is required.
It would seem that within this pathway the so-called ADP receptor P2Y12 is the receptor that is blocked by clopidogrel whereas aspirin acts within the cell in the uricadonic acid cascade that will block thromboxane release. Dipyridamole is also thought to act in the same way though clearly not as well given the lesser effect of dipyridamole.
It is worth considering the history of stroke prevention. In 1977 there were no proven strategies. In 1978 aspirin was first found effective. In 1987 aspirin and dipyridamole was shown beneficial.
In 1991 carotid endarterectomy where there was a greater than 70% stenosis was proved effective. In 1993 warfarin was considered useful. In 1996, clopidogrel first emerged as an effective agent in stroke reduction.
It is only as recent as 2001 that reduction in blood pressure and then the reduction of cholesterol with the use of statins in 2006 emerged.
The anti-platelet TRIALIST collaboration assessed more than 200,000 patients. This showed that anti-platelet agents generated a reduction in vascular events of about 25%. This included stroke, myocardial infarction or any vascular deaths.
Since these results were published in 2002, a whole series of further studies have reported.
Clopidogrel was tested against aspirin in the CAPRIE trial (clopidogrel versus aspirin in patients at risk of ischaemic events reporting in 1996. This showed that clopidogrel was superior to aspirin in preventing MI, stroke or vascular death but the difference was small.
The ESPRIT trial (European/Australasian stroke prevention in reversible ischaemia trial) looked at the use of aspirin versus aspirin plus dipyridamole and that the combination was superior to aspirin alone by 20%. This benefit however was only seen after two years. 40% of the patients could not tolerate the dipyridamole usually because of headache.
The MATCH study in 2004 tested clopidogrel versus aspirin plus clopidogrel. The basis of this was the use of clopidogrel in unstable angina as was shown in the CURE trial. Many patients had multiple risk factors as well as cerebro-vascular disease and the combination treatment was not better than clopidogrel alone. There was also double the number of intra-cerebral haemorrhages in the combination group. It was this study that led to the view that combination therapy should be used routinely after stroke.
The CHARISMA trial (Clopidogrel for high athero-thrombotic risk of ischaemic stabilisation management and avoidance) also looked at a range of vascular disease and patients with multiple risk factors. The combination was once again not more effective than aspirin but there was no difference in intra-cerebral haemorrhages although other types of haemorrhage were more common.
Some authors however have concluded that clopidogrel plus aspirin was more beneficial than aspirin alone.
When patients who had risk factors and no disease were excluded however leaving those patients who had symptoms and were symptomatic, then it was apparent that the combination generated a 20% reduction compared to aspirin alone. The use of a sub-group analysis however has been criticised as this was not the initial intention within the primary trial.
With the PROFESS trial, clopidogrel was compared to aspirin plus dipyridamole and there was no difference between the two groups.
In all of the trials, it has been identified that the stroke risk is going down because there is more aggressive treatment of high blood pressure and the lipid profile.
In a Chinese trial, patients randomised within six hours of a stroke had the greatest benefits with the use of aspirin.
The FASTER trial (the fast assessment of stroke and transient ischaemic attack to prevent early recurrence) has shown the combination of clopidogrel plus aspirin was beneficial compared to aspirin alone in preventing early recurrent events.
A number of trials have also examined anti-coagulation and with the exception of atrial fibrillation, there is no benefit compared to aspirin.
Having said that, it is also recognised that 35 – 40% of strokes occur in people already taking aspirin and its efficacy as identified in numerous trials now is low. Although it has a 20 – 25% reduction of risks in cardiac disease, it is only 15 – 20% effective for patients with cerebro-vascular disease.
There is the concept of aspirin resistance as well as aspirin failure and unfortunately in standard clinical practice, it is not possible to determine aspirin resistance very easily.
It was also confusing in that the PROFESS study showed that aspirin plus dipyridamole generated more intra-cranial bleeds and haemorrhagic events than in the clopidogrel group alone.
The PROFESS study also demonstrated that clopidogrel was tolerated far better than the combined treatment. This has led some authorities to consider that clopidogrel was the preferred initial therapy because it has a greater efficacy than aspirin and is better tolerated and that it is safer and better tolerated than aspirin and dipyridamole.
Aspirin and clopidogrel it is said should only be used if all else fails and that would be based on the MATCH results and the sub-group analysis in CHARISMA. The combination however is associated with more bleeding in stroke patients and at the moment it is not recommended by the American Heart Association stroke prevention guidelines.
Any discussion on the use of clopidogrel in cerebro-vascular disease needs to consider the most recent data on the use of clopidogrel in acute coronary syndromes. Neurologists seem to follow cardiologists albeit some years later in the management of ‘brain attack’ as opposed to ‘heart attack’.
A recent review in the British Medical Journal (BMJ 2009;338998-1002) deals with this in detail.
Clopidogrel is the treatment of choice in the treatment of both non-ST and ST elevation myocardial infarction and in percutaneous coronary intervention. This treatment reduces death, re-infarction and adverse cardiac events.
There has been some discussion about the amount of clopidogrel but the consensus view is that a loading dose of 300mg. should be given followed by 75mg. daily. This treatment should continue for twelve months for non-ST elevation myocardial infarction and fourteen days for ST elevation myocardial infarction.
With a bare metal stent, patients are advised to receive clopidogrel in addition for aspirin ideally for up to one year. With drug eluting stents, aspirin and clopidogrel should be given for at least one year. Clopidogrel however is known to increase bleeding, particularly when in combination with other anti-thrombotic agents.
Clopidogrel mono-therapy has a similar risk of bleeding to that of aspirin mono-therapy. The combination again of clopidogrel and aspirin increase the absolute increase of moderate to major bleeding by about 1%. The dual treatment increases bleeding mostly in the gut.
The authors of the study confirm the ongoing dilemma about the use of aspirin and clopidogrel when there is also a need for warfarin for whatever reason. This increases the risk of bleeding significantly.
Obviously if an individual is allergic to aspirin, then clopidogrel should be used indefinitely. When clopidogrel has been used, then if any intercurrent surgery needs to take place then the advice is to stop clopidogrel five days before such surgery or dental extraction, but personal experience actually suggests that ten days may be more suitable. There needs also to be the avoidance of herbal remedies such as ginko because of the increased risk of bleeding.
In conclusion, it is apparent that warfarin with or without pre-heparinisation is vital treatment for the prevention of stroke in individuals who have atrial fibrillation. Clopidogrel is superior to aspirin and seemingly the equivalent of aspirin plus dipyridamole. In some now quite well-defined circumstances, aspirin should be used with clopidogrel as listed above.
Perhaps the main unanswered question for neurologists is what to do if there is symptomatic further stroke or strokes or evidence of cumulative small vessel ischaemic change or embolic infarction on serial MRI brain scans, when an individual has been on aspirin and dipyridamole. Does one just say ‘bad luck’ and do nothing or substitute clopidogrel 75mg. daily. Similarly, if there is failure of stroke control with clopidogrel alone, what should be the preferred treatment and does that include the addition of aspirin, which would seem logical.
Michael Gross MA MD FRCP
A new anti-coagulant, rivaroxaban has now been shown effective and recommended by NICE in preventing venous thrombo-embolism during elective hip or knee replacement surgery. Rivaroxaban was shown to be superior to enoxaparin with an absolute reduction of 3.19% in the risk of a primary outcome event. There was no difference in major, non-major or any bleeding between the study groups. At present this obviously does not impact on neuro-vascular or cardio-vascular disease but it is an agent to watch as further trials emerge.
Aspirin with or without dipyridamole does not reduce cardio-vascular events in individuals with peripheral artery disease. It does however significantly reduce non-fatal stroke events in those patients. No increased risk of bleeding was seen.
It is an interesting reflection that the use of aspirin in peripheral arterial disease has generated trials, the largest of which has included only 1276 people, whereas the trials of cardio-vascular and neuro-vascular disease have enrolled literally tens of thousands of patients.
Although outside the primary brief of the anti-thrombotic agent review, it is well recognised that carotid endarterectomy has a role to play in stenoses of the carotid circulation greater than 70%. When all goes well, patients will be discharged often within forty-eight hours of the procedure, which can be carried out by local anaesthetic. 1 – 2% of patients will develop severe hypertension and seizures and may have a new neurological deficit.
One of the difficulties in the trials is that the North American and European TRIALIST assessment of the degree of carotid stenosis was not concordant.
It is apparent that the best absolute risk reduction is when the stenosis is between 70% and 99% when the absolute was 15.6%. The figures however also suggested that there was benefit for stenosis between 50% and 69% though it was at this level of stenosis that the North American and European groups were perhaps most discordant with a 50% stenosis in the NASCET study, being broadly equivalent to a 75% stenosis in the ECST.
The UK has been very poor in assessing patients with neuro-vascular disease. In 1997, the UK audit of carotid endarterectomy showed the median delay from onset of symptoms to surgery was 189 days. In 2004, the Royal College of Physicians sentinel audit showed only 50% of patients with a transient ischaemic attack had undergone a duplex ultrasound examination within twelve weeks. By 2007, the delay from referral to surgery had fallen to 45 days.
The current views on high risk of stroke include the following:-
A number of imaging features have also been identified as carrying a higher risk as follow:-
It also used to be thought that an individual with a transient ischaemic attack needed to wait some six to eight weeks before carotid surgery but this has been doubted in recent reviews which have shown that there is not an excessive increase in risk by early surgery.
Finally, the view that older patients did not benefit from carotid endarterectomy has been thoroughly disproved in the NASCET trial showing that patients older than 75 gained more benefit from carotid endarterectomy than any other age group.