Quiz feedback: Antihypertensives, warfarin and clopidogrel

Thiazide diuretics remain a good first choice antihypertensive for many patients. The New Zealand guidelines recommend a low dose thiazide as first-line treatment unless contraindicated or if indications are present for one of the other treatment options.

Beta blockers are not usually considered first line for the treatment of hypertension unless there is another important indication for their use such as angina or rate control.

It is not necessary to increase the dose of a single agent to the maximum before considering combination treatment. There is an additive or even synergistic effect when two antihypertensives from different classes are combined, which is greater than the effect of increasing the dose of a single medicine. A combination of two agents at low doses may be better tolerated than a single agent at maximum dose.

Older people tend to have lower plasma renin activity than younger people therefore ACE inhibitors and beta blockers may not be as effective. Several guidelines recommend that ACE inhibitors are initiated for people aged under 55 years with hypertension.

A combination of antihypertensive medicines is required by most patients to reach their treatment target so the initial choice of agent is less important than overall blood pressure reduction.

A thiazide diuretic is effective in reducing blood pressure in people with angina but there are good reasons to use other agents; beta blockers for rate control, calcium channel blockers for rate control and/or coronary vasodilatation or an ACE inhibitor for cardioprotective effects to slow progression to heart failure.

An ACE inhibitor would normally be considered a first-line agent in a person with chronic kidney disease because of its reno-protective effects. ACE inhibitors (and angiotensin receptor blockers) significantly reduce proteinuria and improve renal and cardiovascular outcomes in people with chronic kidney disease.

Thiazide diuretics and beta blockers have both been associated with an increased risk of new-onset diabetes. However, they are not contraindicated in patients with diabetes and they are unlikely to significantly affect glycaemic control. Most guidelines advise that thiazides and beta-blockers are used with caution in diabetes, and usual monitoring will detect any changes in glycaemic control.

The risk of adverse metabolic effects with thiazides is mainly associated with high doses. The combination of an ACE inhibitor and a low dose thiazide is still beneficial in people with diabetes. However, the combination of a thiazide diuretic with a beta blocker, while effective, is not routinely recommended due to the potential for additive adverse metabolic effects.

The bleeding risk with warfarin is greatest in people who have not previously received warfarin, and in the first three months of treatment. Increased bleeding risk is not associated with previous exposure to warfarin or other anticoagulants.

Older people are generally more sensitive to the effects of medicines and starting with a low dose of warfarin and carefully titrating until the target INR is reached are especially important. A lower maintenance dose is often required. Other factors related to aging such as confusion, forgetfulness, increased risk of spontaneous bleeding and other pathological changes increase the potential for bleeding complications in older people taking warfarin.

Intracranial haemorrhage is relatively uncommon but is the most serious complication of anticoagulation related bleeding, with a mortality rate of up to 50%. Patients who initially survive an intracranial bleed are likely to have significant functional deficits or to die within one month. Extracranial bleeds are much more likely and range from serious gastrointestinal bleeds to relatively minor bleeding events.

People aged greater than 75 years and/or those with uncontrolled hypertension or previous ischaemic stroke, are all at increased risk of stroke and intracranial haemorrhage.

There is good evidence that statins are effective in reducing the risk of stroke but the evidence for the effect on the risk of intracranial haemorrhage is conflicting. Patients randomised to atorvastatin in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial had an increased incidence of intracranial haemorrhage, a finding contrary to accumulated evidence from other randomised trials that suggested no increased incidence.

Recent studies have shown a link between low vitamin D levels and increased stroke risk and there is increasing interest in the role of vitamin D status and the risk of cardiovascular diseases. There is no evidence of an association between low vitamin D status and risk of intracranial haemorrhage.
http://stroke.ahajournals.org/cgi/content/full/39/7/2151

A number of factors have been associated with increased bleeding risk in older people taking warfarin. These include; concurrent use of aspirin, other antiplatelet medicines and NSAIDs, diabetes and other co-morbidities, alcohol or drug misuse, polypharmacy (increased risk of drug interactions) confusional states and poor knowledge of warfarin use. INR values above the therapeutic range will increase bleeding risk which emphasises the need for careful monitoring.

Not all respondents correctly identified that diabetes increases the risk of bleeding complications. Elevated blood glucose levels can result in blood vessel deformities (thickening and twisting), causing them to leak.

Thiazide diuretics do not adversely interact with warfarin.

There is insufficient evidence to support the use of clopidogrel for the primary prevention of CVD and it is not licensed for this indication. Some of the main indications for clopidogrel are when aspirin is contraindicated or not tolerated, for example, secondary prevention of CVD.

Clopidogrel is indicated in the secondary prevention of stroke (as selected by a quarter of respondents) however, clopidogrel should be administered alone in this circumstance. The combination of aspirin and clopidogrel post-stroke is not recommended due to increased bleeding risk.

In acute coronary syndrome without ST-elevation and post angioplasty, the most effective treatment is the combination of aspirin and clopidogrel, but clopidogrel alone is an effective alternative if aspirin cannot be used. Clopidogrel appears to be equally effective as an aspirin plus dipyridamole combination for the secondary prevention of stroke/TIA and can be considered as an alternative.

The usual maintenance dose of clopidogrel in primary care is 75 mg daily. A loading dose of 300 mg or more may be given in secondary care.

Generally, the dose of clopidogrel does not need to be adjusted in renal impairment. However, experience of the use of clopidogrel in severe renal impairment is limited and caution is required if clopidogrel is used in these patients. Clopidogrel is not recommended in patients with severe hepatic impairment.

The risk of bleeding with clopidogrel appears to be slightly lower than with low dose aspirin but the difference is small. Clopidogrel has similar antiplatelet effects to aspirin and it takes seven to ten days for full recovery of platelet function after the last dose.

It is well recognised that NSAIDs increase bleeding risk and this will be exacerbated if they are given with an antiplatelet drug such as clopidogrel or aspirin. Serotonin re-uptake inhibitors (SSRIs) such as fluoxetine increase the risk of bleeding by an effect on platelet serotonin. Recent studies have shown that bleeding risk is increased if SSRIs are given with NSAIDs. Formal studies have not been performed, but it is reasonable to assume that if an SSRI is given with clopidogrel, bleeding risk will be at least additive.

Some studies have shown that the risk of upper GI haemorrhage is increased with the combination of oral corticosteroids and aspirin and there may be a similar increased risk if the combination of clopidogrel with a corticosteroid is used.

There is no evidence that beta-blockers or omeprazole increase bleeding risk if given with clopidogrel.