ASPIRIN: the best NSAID

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ASPIRIN REDUCES CORONARY THROMBOSIS 51%


Aspirin 324 mg (compared to placebo) for high risk group, it lowered death 51%, and aspirin lowered acute myocardial infraction (MI) 51%.  Current standard recommended dosage is 1/3 that amount (85 mg), which is a practice contrary to the totality of evidence.  Moreover much better results are obtained when those who are resistant to the anti-coagulant effect of aspirin are given a higher dose—see bottom article.     

Protective Effects of Aspirin against Acute Myocardial Infarction and Death in Men with Unstable Angina — Results of a Veterans Administration Cooperative Study

New England Journal of Medicine

N Engl J Med 1983; 309:396-403 August 18, 1983,   http://www.nejm.org/doi/pdf/10.1056/NEJM198308183090703

Abstract

We conducted a multicenter, double-blind, placebo-controlled randomized trial of aspirin treatment (324 mg in buffered solution daily) for 12 weeks in 1266 men with unstable angina (625 taking aspirin and 641 placebo). The principal end points were death and acute myocardial infarction diagnosed by the presence of creatine kinase MB or pathologic Q-wave changes on electrocardiograms. The incidence of death or acute myocardial infarction was 51 per cent lower in the aspirin group than in the placebo group: 31 patients (5.0 per cent) as compared with 65 (10.1 per cent); P = 0.0005. Nonfatal acute myocardial infarction was 51 per cent lower in the aspirin group: 21 patients (3.4 per cent) as compared with 44 (6.9 per cent); P = 0.005. The reduction in mortality in the aspirin group was also 51 per cent — 10 patients (1.6 per cent) as compared with 21 (3.3 per cent) — although it was not statistically significant; P = 0.054. There was no difference in gastrointestinal symptoms or evidence of blood loss between the treatment and control groups.

Our data show that aspirin has a protective effect against acute myocardial infarction in men with unstable angina, and they suggest a similar effect on mortality. (N Engl J Med 1983; 309:396–403

http://www.nejm.org/action/showImage?doi=10.1056%2FNEJM198308183090703&iid=f001  FIGURE 1

http://www.nejm.org/action/showImage?doi=10.1056%2FNEJM198308183090703&iid=t001  TABLE 1  

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High dose aspirin (1.5 g/day) lowers death 42%, and non-fatal MIs were 54% lower

http://ukpmc.ac.uk/abstract/MED/6777073  UK  PUBMED CENTRAL,

The German-Austrian aspirin trial: a comparison of acetylsalicylic acid, placebo and phenprocoumon in secondary prevention of myocardial infarction. On behalf of the German-Austrian Study Group.

 

Abstract

In a multicenter clinical trial on the prevention of recurrent myocardial infarction, 946 patients who had survived a myocardial infarction for 30-42 days were randomly allocated to acetylsalicylic acid (ASA, 1.5 g/day) (317 patients), placebo (309 patients) or phenprocoumon treatment (320 patients) and were followed to determine the incidence of total mortality, coronary death and nonfatal recurrent myocardial infarction. The ASA and placebo groups were treated in double-blind fashion. The observation period for each patient was 2 years. Total mortality was lower in the ASA group (27 patients) than in the placebo (32 patients) and phenprocoumon groups (39 patients). There were 13 coronary deaths (fatal myocardial infarction and sudden death) in the ASA group, 22 in the placebo group and 26 in the phenprocoumon group. This represents a reduction rate of 42.3% in the ASA group compared with placebo (p less than 0.1) and of 46.3% in the ASA group with phenprocoumon (p approximately 0.07). Considering male patients alone, the difference regarding coronary death is significant between ASA vs placebo (p less than 0.05, reduction rate 56.4%) and ASA vs phenprocoumon (p less than 0.05, reduction rate 55.6%). Coronary events (coronary death and nonfatal recurrent myocardial infarctions) were lower in the ASA group (24 events) than in the placebo (37 events) (p less than 0.07) or phenprocoumon group (32 events).

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Effectiveness of aspirin therapy proportional to the ability to suppress  blood clots as measured by effect on 11-dehydrothromboxane B2,   The highest quartile compared to the lowest had a 3,5 times greater risk of death.  Given the benefits of aspirin and the significantly greater side effects of alternative drugs, the prudent choice would be to increase the dosage of aspirin; however the drug industry recommends according to their vested interest. 

American Heart Association

Aspirin-Resistant Thromboxane Biosynthesis and the Risk of Myocardial Infarction, Stroke, or Cardiovascular Death in Patients at High Risk for Cardiovascular Events

http://circ.ahajournals.org/content/105/14/1650.short

2002; 105: 1650-1655 Published online before print March 25, 2002doi: 10.1161/​01.CIR.0000013777.21160.07

Abstract

Background— We studied whether aspirin resistance, defined as failure of suppression of thromboxane generation, increases the risk of cardiovascular events in a high-risk population.

Methods and Results— Baseline urine samples were obtained from 5529 Canadian patients enrolled in the Heart Outcomes Prevention Evaluation (HOPE) Study. Using a nested case-control design, we measured urinary 11-dehydro thromboxane B2 levels, a marker of in vivo thromboxane generation, in 488 cases treated with aspirin who had myocardial infarction, stroke, or cardiovascular death during 5 years of follow-up and in 488 sex- and age-matched control subjects also receiving aspirin who did not have an event. After adjustment for baseline differences, the odds for the composite outcome of myocardial infarction, stroke, or cardiovascular death increased with each increasing quartile of 11-dehydro thromboxane B2, with patients in the upper quartile having a 1.8-times-higher risk than those in the lower quartile (OR, 1.8; 95% CI, 1.2 to 2.7; P=0.009). Those in the upper quartile had a 2-times-higher risk of myocardial infarction (OR, 2.0; 95% CI, 1.2 to 3.4; P=0.006) and a 3.5-times-higher risk of cardiovascular death (OR, 3.5; 95% CI, 1.7 to 7.4; P<0.001) than those in the lower quartile.

Conclusions— In aspirin-treated patients, urinary concentrations of 11-dehydro thromboxane B2 predict the future risk of myocardial infarction or cardiovascular death. These findings raise the possibility that elevated urinary 11-dehydro thromboxane B2 levels identify patients who are relatively resistant to aspirin and who may benefit from additional antiplatelet therapies or treatments that more effectively block in vivo thromboxane production or activity.

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The lower rates in these studies can be attributed to the lower dose of aspirin


http://www.aspirin-foundation.com/uses/cardio/thrombosis.html

  Aspirin and Coronary Thrombosis

 

Once the anti-aggregant effect of aspirin on platelets had been described in the mid 1960s, calls for trials of aspirin in myocardial infarction were made by John O’Brien in the UK (19) and by Harvey Weiss and others in the USA.21

In fact, these calls had been anticipated. Laurence Craven, a family practitioner in Glendale, California, published a series of three papers on aspirin in the early 1950’s (22-24).  Each of these focused on some aspect of bleeding.

In the first, Craven pointed out that women take aspirin rather often for their pains and aches, while men tend to scorn such an ‘effeminate’ remedy and he went on to wonder if this difference might explain the sex difference in the incidence of heart attacks. (22) In his second paper,

Craven described bleeding in tonsillectomy patients given Aspergum, a mint flavoured gum impregnated with aspirin. (23) His third paper reports uncritically a remarkable benefit of aspirin on heart attacks and strokes (see panel). Craven’s ideas were however so unacceptable at that time, and his experimental work so flawed that he had difficulty reporting his findings and had to submit his papers to a rather obscure journal. (24)

Craven died of an MI a few years later.
The calls of O’Brien and Weiss were however heard in the MRC Epidemiology Unit in Cardiff, and in 1969 a double-blind placebo-controlled randomised trial of low-dose aspirin was commenced. (25) Men who had been recently discharged from local hospitals following an MI were invited to cooperate. Those who agreed were randomised to receive either 300 mg aspirin in a gelatine capsule or a placebo capsule.

Two points about the published report on this first trial are worth noting (see panel below). First, the journal published it under the headline: ‘For debate’. This was totally appropriate. Clinical practice should never be based on the results of a single trial, however convincing these are.

Replication is essential and if a drug or a preventive measure truly works then it will show in different patient groups, in different situations and in trials run by different trialists. Secondly, the results of the trial were evaluated only in terms of a reduction in total deaths. The inclusion of non-fatal events gives opportunity for bias due to a possible differential reporting of symptoms. Cardiovascular disease makes a substantial contribution to all-cause deaths, and if a measure does reduce it, an effect on total mortality should be seen.

For debate
A Randomised Controlled Trial of Acetyl Salicylic Acid in the Secondary Prevention of Mortality from Myocardial Infarction.

P.C.Elwood, A.L.Cochrane, M.L.Burr, P.M.Sweetnam, G.Williams, E Welsby, S.J.Hughes, R.Renton
British Medical Journal 1974,1, 436-440

Summary
The results of a randomised controlled trial of a single daily dose of acteyl salicylic acid (aspirin) in the prevention of re-infarction in 1,239 men who had had a recent myocardial infarct were statistically inconclusive. Nevertheless, they showed a reduction in total mortality of 12% at six months and 12% at twelve months after admission to the trial. Further trials are urgently needed to establish whether or not the effect is real.

Naturally, clinicians at that time were somewhat more than sceptical of the whole situation, and there was no detectable change in clinical practice. However research groups around the world took note, a number of trials were set up and by 1980 six trials had been reported. (25-30)

An early overview (Seoul conference on aspirin 1980)
TRIAL No of patients Reduction by aspirin


Cardiff 1 (1974)25 1239 26% n.s.
CDP (1976) 26 1529 30% n.s.
Cardiff 2(1979)27 1725 30% n.s.
German (1979)28 626 18% n.s.
AMIS (1980)29 4524 10% n.s.
PARIS (1980)30 1216 18% n.s.

These trials involved 10,859 patients, and the weighted overall effect was:

23% reduction by aspirin (P < 0.0001)

Each of these early trials suggested a beneficial effect of aspirin, but the results of none achieved an acceptable level of statistical significance. Overall, however, there is clearly convincing evidence of benefit.

The reporting of overviews of the results from all relevant published trials relating to a particular clinical intervention is becoming increasingly common throughout clinical practice and the first such overview, or meta-analysis, based on these six trials was presented by Richard Peto and his colleagues of Oxford to the inaugural meeting of the Society for Clinical Trials in Philadelphia in 1980.(31)

This overview was one strand in the thinking that led eventually to the setting up of the Cochrane Collaboration, the worldwide initiative that aims to conduct overviews within every area of clinical activity. (32)

Since that first report, the Oxford group have produced several monumental overviews of aspirin and cardiovascular disease: in 1988 (33) ,1994 (34). and 1997 (35).

The following is based on the overview published in 1994, which combines results from 145 RCTs, with a total of 102,459 patients and 10,943 outcome events. A remarkably consistent reduction in vascular events is demonstrated (22 to 32%).

An overview of RCT's of aspirin and cardiovascular disease

(BMJ 1994;308:81-106)

Patient group No. of trials Reduction in MI stroke or vasc. death.
Prior MI 11 25%
Acute MI 9 29%
Prior stroke/TIA 18 22%
Other high risk 104 32%

All trials 25%

Patient group No. of trials Reduction in MI stroke or vasc. death.
Non-fatal MI 122 34%
Non-fatal stroke 124 25%
Vascular death 144 17%
All-cause death 144 16%

Also considering the following factors
male/female; under/over 65yrs; hypertensive / normotensive; diabetic / non-diabetic gave no evidence of any significant differences in benefit.

An overview of studies with such a large number of clinical outcomes enables the drawing of conclusions from sub-group analyses with a fair degree of confidence. The benefit of aspirin is similar in all groups of patients whatever the prior indication for prophylaxis. Furthermore, there is no evidence of differences in the proportionate reduction by aspirin in different patient groups: males and females, older and younger subjects, diabetic and non-diabetic, hypertensive and normotensive subjects etc.

Together with this overview a Press Release by the group in Oxford was widely reported by the media. (36) This gave the estimate that around 100,000 premature deaths from cardiovascular disease could be prevented world-wide by the appropriate use of low-dose aspirin together with at least this number of non-fatal heart attacks and strokes.

 

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Disclaimer:  The information, facts, and opinions provided here is not a substitute for professional advice.  It only indicates what JK believes, does, or would do.  Always consult your primary care physician for any medical advice, diagnosis, and treatment.