Cochrane for Clinicians

Putting Evidence into Practice

Antiplatelet Therapy and Anticoagulation
in Patients with Hypertension

GLENN GRIFFIN, M.D.
United Arab Emirates University Faculty of Medicine and Health Sciences, Al Ain, United Arab Emirates

This clinical content conforms to AAFP criteria for evidence-based continuing medical education (EB CME). EB CME is clinical content presented with practice recommendations supported by evidence that has been systematically reviewed by an AAFP-approved source. The practice recommendations in this activity are available online at http://www.cochrane.org/cochrane/revabstr/AB003186.htm.

The Cochrane Abstract below is a summary of a review from the Cochrane Library. It is accompanied by an interpretation that will help clinicians put evidence into practice. Glenn Griffin, M.D., presents a clinical scenario and question based on the Cochrane Abstract, along with the evidence-based answer and a full critique of the abstract.

Clinical Scenario

A new patient tells you that he read in a men's health magazine that people with hypertension should take daily aspirin. He asks if you agree.

Clinical Question

Should we prescribe antiplatelet agents or anticoagulants for all patients with hypertension?

Evidence-Based Answer

Antiplatelet agents should not be used in patients with hypertension and no previous history of heart attack or stroke. However, these agents are recommended for use in hypertensive patients who already have vascular disease. Anticoagulants should not be used for prevention of vascular events, alone or in combination with acetylsalicylic acid (ASA),
in patients with elevated blood pressure. Currently, there is not enough evidence to recommend the use of glycoprotein IIb/IIIa inhibitors, ticlopidine, or clopidogrel for primary prevention of vascular events.

Cochrane Abstract Background. Elevated systemic blood pressure results in high intravascular pressure. The main complications, coronary heart disease, ischemic strokes, and peripheral vascular disease, are related to thrombosis rather than hemorrhage. Some complications related to elevated blood pressure, heart failure, and atrial fibrillation are associated with stroke and thromboembolism. It seems plausible that antithrombotic therapy may be particularly useful in preventing thrombosis-related complications of elevated blood pressure. Objectives. To conduct a systematic review of the role of antiplatelet therapy and anticoagulation in patients with hypertension, including those with elevations in systolic and diastolic blood pressure and those with isolated elevations of systolic or diastolic blood pressure. The following hypotheses were addressed: (1) antiplatelet agents reduce total deaths and major thrombotic events compared with other active treatment or placebo; and (2) oral anticoagulants reduce total deaths and major thromboembolic events compared with other active treatment or placebo. Search Strategy. The authors1 studied reference lists of articles found by searching electronic databases (MEDLINE, EMBASE, DARE) and abstracts from national and international cardiovascular meetings. Relevant authors of these studies were contacted to obtain further data. Selection Criteria. Randomized controlled trials (RCTs) in patients with elevated blood pressure were included if they were of at least three months' duration and compared antithrombotic therapy with other active treatment or placebo. Data Collection and Analysis. Data were independently collected and verified by two reviewers. Data from different trials were pooled when appropriate. Primary Results. The Antiplatelet Trialists' Collaboration meta-analysis of antiplatelet therapy for secondary prevention in patients with elevated blood pressure reported a 4.1 percent absolute reduction in vascular events compared with placebo. Data on the patients with elevated blood pressure from the 29 individual trials were requested but could not be obtained. Three additional trials met the inclusion criteria and were included. Acetylsalicylic acid (ASA) did not reduce stroke or "all cardiovascular events" compared with placebo in primary prevention patients with elevated blood pressure and no prior cardiovascular disease. In one large trial (the Hypertension Optimal Treatment trial), ASA taken for five years reduced rates of myocardial infarction (MI) (absolute risk reduction, 0.5 percent; number needed to treat [NNT], 200 for five years), increased rates of major hemorrhage (absolute risk increase, 0.7 percent; NNT, 154), and did not reduce all-cause mortality or cardiovascular mortality. In the Clopidogrel vs. Aspirin in Patients at Risk of Ischemic Events trial, there was no significant difference between ASA and clopidogrel for the composite end point of stroke, MI, or vascular death. In two small trials, warfarin alone or in combination with ASA did not reduce rates of stroke or coronary events. Reviewers' Conclusions. Antiplatelet therapy with ASA cannot be recommended for primary prevention of vascular events in patients with elevated blood pressure, because the magnitude of benefit-a reduction in rates of MI-is negated by a harm of similar magnitude, an increase in rates of major hemorrhage. Antiplatelet therapy is recommended for secondary prevention in patients with elevated blood pressure because the magnitude of the absolute benefit is many times greater.2 Warfarin therapy alone or in combination with aspirin in patients with elevated blood pressure cannot be recommended because of lack of demonstrated benefit. Glycoprotein IIb/IIIa inhibitors, as well as ticlopidine and clopidogrel, have not been evaluated sufficiently in patients with elevated blood pressure. Further trials of antithrombotic therapy with complete documentation of all benefits and harms are needed in patients with elevated blood pressure.   These summaries have been derived from Cochrane reviews published in the Cochrane Database of Systematic Reviews in the Cochrane Library. Their content has, as far as possible, been checked with the authors of the original reviews, but the summaries should not be regarded as an official product of the Cochrane Collaboration; minor editing changes have been made to the text (www.cochrane.org).

Practice Pointers

This review shows that aspirin should be used for prophylaxis only in patients with hypertension and a history of stroke, transient ischemic attack, myocardial infarction (MI), angina, or peripheral vascular disease. An appropriate choice and dosage of antiplatelet agent for secondary prevention would be
75 or 81 mg of enteric-coated ASA daily.2

The primary analysis of the review is based on four large, high-quality trials. Some additional analysis is based on a previous meta-analysis of prolonged antiplatelet therapy compared with placebo. The four trials were analyzed and discussed individually. Results were consistent among studies and were measured with reasonable precision.

The authors were careful to assess benefit and harm for each intervention. This is why prescribing an antiplatelet agent or anticoagulant is not recommended for primary prevention of adverse vascular events in patients with hypertension. In the case of antiplatelet agents, the benefit (reduction in rates of MI) was balanced by a harm (increase in major hemorrhagic events), resulting in no overall decrease in all-cause or cardiovascular mortality. No benefit was observed for anticoagulants. There is not enough evidence to recommend for or against the use of ticlopidine, clopidogrel, and glycoprotein IIb/IIIa inhibitors. However, they should not be used for primary prevention of vascular events in hypertensive patients because they are expensive and provide no significant benefit.

There is evidence from the Antiplatelet Trialists' Collaboration meta-analysis3 that ASA in patients with a history of vascular disease for secondary prevention of major adverse events provides a benefit that outweighs the risk of harm and the cost of the medication. However, no subgroup analysis was done to assess the benefit and harm from prolonged low-dosage ASA in hypertensive patients with a history of gastrointestinal bleeding.4 Therefore, there is insufficient evidence to recommend prolonged low-dosage ASA for secondary prevention in such patients. In patients for whom ASA would provide benefit but is contraindicated, clopidogrel would serve equally well for secondary prevention of adverse vascular events. It should not be used as first-line therapy because it is expensive and no more effective than ASA.

A search of the National Guideline Clearinghouse in October 2004 found no guidelines that discussed the use of antiplatelet agents or anticoagulants in the management of hypertension. The Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure5 does not address the use of antiplatelets or anticoagulants. This Cochrane review is the best and most up-to-date information available on this topic at this time. Clinical Evidence6 outlines several other effective measures for the secondary prevention of adverse vascular events. The ones that are of interest to family physicians include beta blockers, angiotensin-converting enzyme inhibitors, cholesterol reduction, smoking cessation, the Mediterranean diet, eating more fish, managing stress, and getting regular exercise.

The Author

Glenn Griffin, M.D., is associate professor of family medicine at United Arab Emirates University, Al Ain. Dr. Griffin received his medical degree from the University of Toronto Faculty of Medicine and is board certified in family medicine in the United States and Canada.

Address correspondence to Glenn Griffin, M.D., United Arab Emirates University, P.O. box 17666, Al Ain, United Arab Emirates (e-mail: griffing@uaeu.ac.ae). Reprints are not available from the author.

REFERENCES

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Cochrane Briefs

Insulin Monotherapy vs. Combination Therapy

Clinical Question

Are combinations of insulin and oral agents more effective than insulin monotherapy in patients with type 2 diabetes mellitus?

Evidence-Based Answer

NPH insulin and metformin taken at bedtime appears to be the most favorable combination studied, but this conclusion is based on poor-quality, inconsistent studies that measure disease-oriented outcomes. There are no data on the effect of these drug combinations on patient-oriented outcomes.

Practice Pointers

Goudswaard and colleagues identified 20 randomized controlled trials (RCTs) with a total of 1,811 patients. The RCTs included 28 comparisons of insulin monotherapy with a combination of insulin and a sulfonylurea, metformin, or both. About one half of the patients were women. The mean age was 60 years, and patients had type 2 diabetes for a mean of
10 years. None of the studies assessed diabetic complications, diabetes-related mortality, or total mortality. In the United Kingdom Prospective Diabetes Study, treatment of overweight patients with insulin or sulfonylureas had no effect on individual or aggregate microvascular or macrovascular outcomes (36.8 versus 38.9 events per 1,000 patient years).1,2

The identified RCTs were fair quality, with a mean score of 2.8 on a seven-point quality scale. Most did not clearly describe how patients were allocated to treatment groups, and 11 RCTs did not blind patients, physicians, or persons evaluating outcomes. A variety of regimens were compared, and results were combined where appropriate. Differences between insulin monotherapy and combination approaches generally were small and inconsistent. The combination of an oral agent and insulin typically resulted in a slightly lower hemoglobin A1C level (0.1 to 0.4 percent), a difference that is unlikely to be clinically important. Patients taking the combination of insulin and metformin were less likely to gain weight than those taking insulin alone, but this combination was examined only in a single, relatively small RCT. There was no difference between groups in the likelihood of symptomatic hypoglycemia.

MARK H. EBELL, M.D., M.S.

Goudswaard AN, et al. Insulin monotherapy versus combinations of insulin with oral hypoglycaemic agents in patients with type 2 diabetes mellitus. Cochrane Database Syst Rev 2004;(4):CD003418.

REFERENCES

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Use of Beta Agonists in Preterm Labor

Clinical Question

Do betamimetics (i.e., beta agonists) improve outcomes for women with preterm labor?

Evidence-Based Answer

Treatment with betamimetics decreases the number of women with preterm labor who give birth within 48 hours, but it does not decrease the number of births within seven days. Limited evidence suggests that treatment with betamimetics does not decrease perinatal death or morbidity.

Practice Pointers

Betamimetics commonly are used to decrease uterine contractions in women with preterm labor. However, they may cause discomfort and life-threatening adverse effects such as pulmonary edema and hypokalemia. Anotayanonth and colleagues identified 11 randomized controlled trials of betamimetics in 1,332 women with preterm labor.

Compared with placebo, the betamimetic ritodrine significantly decreased the number of women who give birth within 48 hours (23 versus 39 percent; relative risk [RR], 0.63; 95 percent confidence interval [CI], 0.53 to 0.75). This corresponds to a number needed to treat of 6.
It also reduced the risk of delivery within seven days. This benefit did not persist after the authors performed a sensitivity analysis with a random-effects model.

Most of the participants were at 32 weeks' gestation or more. Maternal adverse effects included chest pain, dyspnea, tachycardia, palpitations, tremor, headache, hypokalemia, hyperglycemia, nausea and vomiting, and nasal stuffiness. The RR for cessation of treatment because of adverse events was 11.3 (95 percent CI, 3.8 to 33.5). There was no difference in the rate of perinatal and neonatal deaths. Treatment had no effect on neonatal morbidity such as respiratory distress syndrome, cerebral palsy, and necrotizing enterocolitis. Two trials comparing ritodrine with terbutaline in 183 women found that patients who took terbutaline had a higher incidence of hyperglycemia. There was no difference in maternal or neonatal outcomes.

Although no improvement in infant outcomes was found in this review, most of the trials were done before antenatal corticosteroids were used routinely. Also, most of the trials were done in university hospitals. More studies must be done to determine if a 48-hour delay in delivery to allow for patient transfer and a course of corticosteroids improves outcomes. In the meantime, a short trial of tocolysis for preterm labor is reasonable if corticosteroids or transfer is indicated.

CLARISSA KRIPKE, M.D.

Anotayanonth S, et al. Betamimetics for inhibiting preterm labour. Cochrane Database Syst Rev 2004;(4):CD004352.

REFERENCES

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