There is evidence that most NSAIDs can increase blood pressurein patients treated with antihypertensives, although some studieshave not found increase to be clinically relevant. In varioussmall studies, indometacin appeared not to reduce hypotensive effects of amlodipine, felodipine, nicardipine, nimodipine orverapamil, but it did in one of two studies with nifedipine, and onestudy with nitrendipine. Similarly, ibuprofen caused a small reduction in antihypertensive effects of amlodipine. Diclofenacand sulindac appear not to interact with nifedipine,nor ibuprofen, naproxen, piroxicam or sulindac with verapamil, nor naproxen with nicardipine. Low-dose aspirin did not alter theantihypertensive effect of felodipine or nifedipine in one study,and long-term aspirin did not alter cardiovascular benefits ofnitrendipine in another. Diclofenac reduces verapamil serum levels and raises those of isradipine,but these changes are probablyunimportant. Two reports describe abnormal bruising and prolonged bleedingtimes in two patients and one healthy subject taking verapamilwith aspirin. There are conflicting reports as to whether or notgastrointestinal bleeding is increased by giving NSAIDs with calcium-channel blockers.
Various large epidemiological studies and meta-analyses of clinical trials have been conducted to assess effect of NSAIDs on blood pressure in patients treated with antihypertensives, and findings of these are summarised in table 1 below,(below). In these studies, NSAIDs were not always associated with an increase in blood pressure, and maximum increase was 6.2 mmHg. The effect has been shown for both COX-2 inhibitors and non-selective NSAIDs. In two meta-analyses,(See reference number 1,2) effects were evaluated by NSAID. The confidence intervals for all NSAIDs overlapped, showing that there was no statistically significant difference between NSAIDs, with exception of comparison between indometacin and sulindac in one analysis (See reference number 2). Nevertheless, an attempt was made at ranking NSAIDs based on means. In one analysis,(See reference number 1) effect was greatest for piroxicam, indometacin, and ibuprofen, intermediate for naproxen, and least for sulindac and flurbiprofen. In other meta-analysis,(See reference number 2) effect was greatest for indometacin and naproxen, intermediate for piroxicam, and least for ibuprofen and sulindac. An attempt was also made to evaluate effect by antihypertensive in one analysis (See reference number 1). The mean effect was greatest for beta blockers,intermediate for vasodilators (includes ACE inhibitors and calcium-channel blockers), and least for diuretics. However, differences between groups were not significant.
The findings of individual clinical and pharmacological studies that have studied effects of aspirin or specific NSAIDs on specific calcium-channel blockers are outlined in subsections below
Felodipine. In Hypertension Optimal Treatment (HOT) study, 18 790 treated hypertensive patients, about 82 % of whom received a calcium-channel blocker, usually felodipine alone or in combination, were also given either aspirin 75mg daily or placebo for an average of 3.8 years. It was found that long-term low-dose aspirin does not interfere with blood pressure-lowering effects of antihypertensive drugs studied (See reference number 3).
Nifedipine. In a small study in 18 patients, low-dose aspirin 100mg daily for 2 weeks did not alter blood pressure lowering effect of nifedipine 30 to 60mg daily, given as a modified-release preparation (See reference number 4).
Nitrendipine. A post-hoc analysis of Syst-Eur trial of nitrendipinebased antihypertensive treatment found no difference in cardiovascular outcome between 861 patients who were also using long-term aspirin (700 patients) and/or other NSAIDs (161) and 2882 patients who had never taken aspirin or NSAIDs. Patients in this trial were randomised to receive nitrendipine,which could be combined or replaced by enalapril, hydrochlorothiazide, or both (See reference number 5).
Unnamed calcium-channel blockers. In a randomised study, use of low-dose aspirin 100mg daily for 3 months did not alter blood pressure control in patients taking calcium-channel blockers or ACE inhibitors, when compared with placebo (See reference number 6).
Hypertensive subjects taking slow-release verapamil 240mg daily had a 26 % reduction in AUC of verapamil when they took diclofenac 75mg twice daily (See reference number 7). The AUC of isradipine 5mg twice daily for a week was unaffected in 18 healthy subjects by a single 50mg dose of diclofenac but maximum serum levels were raised by about 20%
2 Summary of epidemiological studies and meta-analyses of effect of NSAIDs on blood pressure in patients taking antihypertensive drugs
Other NSAID or celecoxib therapy not associated with difficulty in controlling blood pressure,but rofecoxib was (odds ratio 1.38).
antagonised all antihypertensives,but only beta blockers
Among
NSAIDs, only effect of piroxicam was statistically
significant, with piroxicam, indometacin and ibuprofen causing greatest increase, and sulindac and flurbiprofen least.
Hydrochlorothiazide,
furosemide,methyldopa, propranolol
significant) in those on NSAIDs,but DBP did not differ. Findings same if indometacin users removed.
NSAID use was associated with a 29 % increased risk of hypertension in those on antihypertensives,but not in those not on antihypertensives.
mmHg,naproxen 3.7,piroxicam 0.5,decrease in mean arterial pressure with ibuprofen 0.8,sulindac 0.16. The difference between indometacin and sulindac was statistically significant.
Sheridan R,Montgomery AA, Fahey T. NSAID use and BP in treated hypertensives: a retrospective controlled observational study. J Hum Hypertens (2005) 19,445–50.
Wolfe F,Zhao S, Pettitt D. Blood pressure destabilization and edema among 8538 users of celecoxib,rofecoxib, and nonselective nonsteroidal antiinflammatory drugs (NSAID) and nonusers of NSAID receiving ordinary clinical care. J Rheumatol (2004) 31,1143–51.
Johnson AG,Nguyen TV, Day RO. Do nonsteroidal anti-inflammatory drugs affect blood pressure? A meta-analysis. Ann Intern Med (1994) 121,289–300.
Chrischilles EA,Wallace RB. Nonsteroidal anti-inflammatory drugs and blood pressure in an elderly population. J Gerontol (1993) 48,M91–M96.
Johnson AG,Simons LA, Simons J, Friedlander Y, McCallum J. Non-steroidal anti-inflammatory drugs and hypertension in elderly: a community-based cross-sectional study. Br J Clin Pharmacol (1993) 35,455–9.
Pope JE,Anderson JJ, Felson DT. A meta-analysis of effects of nonsteroidal anti-inflammatory drugs on blood pressure. Arch Intern Med (1993) 153,477–84.
was unaffected and pharmacokinetics of diclofenac were unchanged (See reference number 8)
A study in elderly women with hypertension found that diclofenac sodium 25mg three times daily for one week had no effect on control of their blood pressure with nifedipine (See reference number 9)
Fifty-three hypertensive patients had no changes in their blood pressure control with verapamil 240 or 480mg daily when they also took ibuprofen 400mg three times daily for 3 weeks (See reference number 10). However, another study in 12 patients with mild or moderate essential hypertension controlled with amlodipine 10mg daily, found that ibuprofen 400mg three times daily for 3 days increased mean blood pressure by 7.8/3.9 mmHg (See reference number 11).
Indometacin 100mg daily for a week did not significantly affect hypotensive effects of nifedipine 20mg twice daily in 10 patients with mild to moderate essential hypertension (See reference number 12). In contrast, in another study, indometacin 100mg in divided doses over 24 hrs was found to raise mean arterial pressure by 17 to 20 mmHg in 5 out of 8 hypertensive patients taking nifedipine 15 to 40mg daily (See reference number 13).
Five other studies, two in healthy subjects(See reference number 14,15)and 3 in patients with hypertension(See reference number 16-18)found that indometacin did not alter blood pressure-lowering effects of amlodipine,(See reference number 18)felodipine,(See reference number 14,16)nicardipine(See reference number 15) or verapamil (See reference number 17). Similarly, haemodynamic effects of nimodipine 30mg three times daily were not affected to a clinically relevant extent by indometacin 25mg twice daily in 24 healthy elderly subjects, although AUC of nimodipine and its maximum plasma levels were slightly increased (See reference number 19). However,indometacin 25mg three times daily raised systolic and diastolic blood pressure by a mean of 4 mmHg in 15 patients taking nitrendipine 5 to 20mg twice daily (See reference number 20).
Naproxen 375mg twice daily had no effect on pharmacokinetics of verapamil in hypertensive subjects (See reference number 7)
A placebo-controlled study in 100 patients taking nicardipine 30mg three times daily found that naproxen 375mg twice daily caused no clinically relevant changes in control of their blood pressure (See reference number 21)
A study in hypertensive patients given up to 440mg of verapamil daily found that piroxicam 20mg once daily for 4 weeks did not significantly alter antihypertensive effects of verapamil (See reference number 22)
A study in elderly women with hypertension found that sulindac 100mg three times daily for one week had no effect on control of their blood pressure with nifedipine (See reference number 9)
A study in hypertensive patients given up to 440mg of verapamil daily found that sulindac 200mg twice daily for 4 weeks did not significantly alter antihypertensive effects of verapamil (See reference number 22)
The bruising ceased when verapamil was stopped
4.5 minutes while she was taking verapamil,and to 9 minutes while she was taking verapamil and aspirin. A healthy subject taking same dose of verapamil and aspirin observed appearance of new petechiae and her bleeding time rose from a normal 4.5 minutes to more than 15 minutes in presence of both drugs (See reference number 23). An 85-year-old man taking enteric-coated aspirin 325mg daily developed widespread and serious ecchymoses of his arms and legs and a retroperitoneal bleed about 3 weeks after starting verapamil 240mg daily (See reference number 24).
A prospective cohort study(See reference number 25)in 1636 elderly hypertensive patients and a case-control study(See reference number 26) found that calcium-channel blockers were associated with an increased risk of gastrointestinal bleeding compared with beta blockers; in one of studies, verapamil had highest rate of bleeding, followed by diltiazem and nifedipine (See reference number 25). Two studies indicated that gastrointestinal bleeding was not increased by calcium-channel blockers (See reference number 27,28). A post-hoc analysis of Syst-Eur data found that there was no interaction between chronic NSAID intake (81% aspirin) and antihypertensive therapy based on nitrendipine in terms of incidence of gastrointestinal bleeding. Further, results suggested that chronic NSAID therapy tended to be associated with a lower incidence of bleeding in patients taking nitrendipine-based therapy than those on placebo (See reference number 5).
There is some evidence that NSAIDs may increase blood pressure in patients treated with antihypertensives. Possible explanations for this include inhibition of vasodilator and natriuretic prostaglandins in kidney and/or a decrease in vascular or endothelial prostaglandin synthesis resulting in salt retention and vasoconstriction (See reference number 29). In contrast, low-dose aspirin appears not to affect blood pressure-lowering effects of calcium-channel blocker-based antihypertensive therapy (See reference number 3).
The prolonged bleeding times noted with verapamil(See reference number 23)are probably a result of inhibition of platelet aggregation, because calcium-channel blockers interfere with movement of calcium ions through cell membranes, which can affect platelet function. This appears to be additive with effects of other antiplatelet drugs. It was suggested that vasodilation produced by calcium-channel blockers in conjunction with inhibition of platelet aggregation may increase risk of bleeding, or at least prevent normal vasoconstrictive response to bleeding,(See reference number 25) although a protective effect of beta blockers rather than an adverse effect of calcium-channel blockers may also be reason (See reference number 27).
Although several studies exist, evidence for an interaction between calcium-channel blockers and NSAIDs or aspirin is still somewhat inconclusive. Some consider that use of NSAIDs should be kept to a minimum in patients on antihypertensives. The effects may be greater in elderly and in those with blood pressures that are relatively high, as well as in those with high salt intake (See reference number 30). However, others consider that clinical importance of an interaction between NSAIDs and antihypertensives is less than has previously been suggested (See reference number 31). While their findings do not rule out a 2/1 mmHg increase in blood pressure with NSAIDs in treated hypertensives,they suggest that if patients in primary care have inadequate control of blood pressure, other reasons may be more likely than any effect of concurrent NSAIDs (See reference number 31). There is insufficient data at present to clearly differentiate between NSAIDs. Further study is needed.
There is some limited evidence that interaction of NSAIDs with calcium-channel blockers is less than with ACE inhibitors (See reference number 4,16,18)
For effects of NSAIDs on other antihypertensive drug classes see ACE inhibitors, , beta blockers, and thiazide diuretics, .
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| Table 1 Summary of epidemiological studies and meta-analyses of the effect of NSAIDs on blood pressure in patients taking antihypertensive drugs | |||||
|---|---|---|---|---|---|
| Study type | Patients | Antihypertensives | NSAIDs | Findings | Refs |
| Case-control (2005) | 184 cases 762 controls (UK primary care) | Not stated. Median of 2 different drugs. | Ibuprofen (78 cases) Diclofenac (60) Other (25) | BP control in treated hypertensives was not affected by use of NSAIDs. No evidence that either SBP or DBP differed according to type of NSAID. | 1 |
| Retrospective analysis (2004) | 8538 patients with rheumatic disease and hypertension | Not stated | NSAID (1164 patients) Celecoxib (654) Rofecoxib (417) | Other NSAID or celecoxib therapy not associated with difficulty in controlling blood pressure, but rofecoxib was (odds ratio 1.38). | 2 |
| Meta-analysis | 50 randomised | Beta blockers (15) | Indometacin (33 trials) | NSAIDs elevated mean supine BP by 5 mmHg. NSAIDs | 3 |
| (1994) | controlled trials in 771 | Vasodilators (18) | Sulindac (7) | antagonised all antihypertensives, but only beta blockers | |
| patients or healthy | Diuretics (12) | Ibuprofen (5) | was statistically significant (6.2 mmHg). Among the | ||
| subjects | Piroxicam (4) | NSAIDs, only the effect of piroxicam was statistically | |||
| Flurbiprofen (4) | significant, with piroxicam, indometacin and ibuprofen causing the greatest increase, and sulindac and flurbiprofen the least. | ||||
| Case-control | 133 cases | Hydrochlorothiazide, | Ibuprofen (30% of | SBP was about 5 mmHg higher (not statistically | 4 |
| (1993) | 133 controls | furosemide, methyldopa, propranolol | cases) Indometacin (22%) Naproxen (18%) Sulindac (13%) | significant) in those on NSAIDs, but DBP did not differ. Findings the same if indometacin users removed. | |
| Cross-sectional cohort (1993) | 2800 elderly (12% on both an NSAID and antihypertensives) | Not stated | Not stated | NSAID use was associated with a 29 % increased risk of hypertension in those on antihypertensives, but not in those not on antihypertensives. | 5 |
| Meta-analysis | 54 studies with 108 | Not stated | Indometacin (600 | Increase in mean arterial pressure with indometacin 3.6 | 6 |
| (1993) | NSAID treatment arms in 1213 hypertensive patients | patients) Naproxen (72) Piroxicam (51) Ibuprofen (55) Sulindac (277) | mmHg, naproxen 3.7, piroxicam 0.5, decrease in mean arterial pressure with ibuprofen 0.8, sulindac 0.16. The difference between indometacin and sulindac was statistically significant. | ||