Nonsteroidal anti-inflammatory drugs and blood pressure

Authored by Chen-Chang Yang




Outline

 

Introduction

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed categories of drugs worldwide.1-3 They are also frequently purchased as over-the-counter items. In the United States, 20 to 40 million people probably have arthritis, most commonly osteoarthritis, necessitating the treatment with NSAIDs.4-5 The use of NSAIDs is especially common among the elderly. It has been estimated that among those aged 65 years and older in the United States, 10% to 15% take prescribed NSAIDs.6 In Australia, the usage of NSAIDs has been found to be even much higher, reaching 26% of those over 60 years.7

The prevalence and incidence of hypertension also rises with age, from approximately 20% in adults to 30-40% among those over 60 years.7-8 Antihypertensive drugs are currently administered to more than 100 million patients for the control of hypertension worldwide.9 In the United States, hypertension is also prevalent and approximately one third of whites and 40% of blacks older than 65 years have hypertension.10 Among the elderly, in whom the prescriptions of both NSAIDs and antihypertensives are highest, 12 to 20 million people in the United States are estimated to use both classes of drugs concomitantly.5 The simultaneous use of these two drug classes, along with the multitude of medical problems in the elderly population that decrease drug metabolism or require multiple drug therapy, has predisposed these patients to the risk of developing drug-drug or drug-disease interactions.

Over the last two decades, there has been growing concern about probable drug interaction between NSAIDs and antihypertensives. Cases with hypertensive emergency have been reported after taking piroxicam or indomethacin in patients with previously well-controlled hypertension.11-12 Numerous clinical trials and some large observational studies have also been conducted to examine such an effect.7-8, 13-30 In a study of more than 2,000 referred patients receiving NSAIDs and antihypertensive therapy, the frequency of drug interaction causing resistant hypertension was found to be about 1% annually.13 Although it is generally believed that concomitant use of NSAIDs would counteract the effects of antihypertensive therapy in patients with hypertension or even cause hypertension in normotensive persons, there remains much controversy on the mechanisms and magnitude of such an effect.5, 31-32 Moreover, the long-term health impacts of such interaction are still not clearly defined.32

Possible mechanisms of nonsteroidal anti-inflammatory drugs on blood pressure

The definite mechanisms that are responsible for the effects of NSAIDs on blood pressure remain unclear.31-32 However, several mechanisms have been demonstrated to be probably involved in the elevation of blood pressure by NSAIDs.33-50 The most important is the inhibition of cyclooxygenase (COX) which reduces systemic and renal synthesis of prostaglandins (figure 1).33-36 Renal prostaglandins, produced in both the cortex and medulla, exert several effects on blood pressure.5 Prostacyclin (PGI2), a major cortical prostaglandin, can relax vascular smooth muscle and indirectly promote natriuresis by reducing renal glomerular vascular resistance.36-38 PGE2, a principal prostaglandin found in the renal medulla, can cause vasodilatation as well.5, 39 Moreover, PGE2 promotes natriuresis by direct inhibition of the tubular reabsorption of sodium and chloride.5 PGE2 also inhibits tubular responsiveness to vasopressin (antidiuretic hormone), thus favoring free water excretion.40 By inhibiting the synthesis of prostaglandins, various NSAIDs may cause sodium and water retention, worsening hypertension and causing mild edema, even in normal individuals, receiving either high or low sodium diets.41

The intrarenal and extrarenal vasodilatory effects of prostaglandins are important in the regulation of blood pressure.5 Nowak and Wennmalm demonstrated that intravenous infusion of indomethacin could produce a greater than 75% reduction in urinary metabolites of prostaglandin E, a significant increase in renal and splanchnic vascular resistance, and an accompanying rise in mean arterial blood pressure of about 10mmHg.44 These effects could be reversed by the infusion of prostaglandin E1. The renal vasodilatory effects of prostaglandins are especially important in states of renal underperfusion, such as in congestive heart failure or volume depletion, since the reduction of prostaglandins in these conditions can lead to unopposed afferent and efferent arteriolar constriction, reduced glomerular filtration rate, and marked sodium and water retension.32, 36, 45-46

Prostaglandins can also play a role in the hypotensive effect of angiotensin-converting enzyme inhibitors (ACEI). Angiotensin-converting enzyme is identical to kininase II, an enzyme that inactivates a potent vasodilator bradykinin.47 Blocking of this enzyme by ACEI then increases bradykinin levels which allow more bradykinin-mediated release of vasodilatory and natriuretic prostaglandins from renal and other tissues.48-49 It is therefore obvious that inhibition of prostaglandins by NSAIDs can counteract the hypotensive effects of the ACEI.

In addition to the their natriuresis and vasodilatory effects, prostaglandins can operate with the renin-angiotensin-aldosterone system, modulating the release of renin and the vasoconstricting and antidiuretic effects of angiotensin II. Both PGE2 and PGI2 are potent stimulators of renin release, and almost all NSAIDs have also been associated with a decrease in plasma renin activity.36, 50-51 Reduction in plasma renin secretion can act to lower blood pressure and attenuate the hypertensive effects of NSAIDs. This effect, however, is usually more than offset by salt and water retention and loss of vasodilatory capabilities resulting from intra-renal prostaglandin inhibition. The net effects of NSAIDs on antihypertensive drugs are variable increases in blood pressure, with more exaggerated responses in patients with pre-existing low renin activity, i.e. the elderly and blacks.5

NSAIDs may also affect systemic vascular resistance and cardiac output which could be implicated in the elevation of blood pressure. Although the actions of NSAIDs on blood vessels remain not well defined, the reduction of prostaglandins are likely to play a role.32 Prostaglandins possess vasodilatory effects and can alter the vascular responses to sympathetic nerve stimulation. The infusion of PGE2 into the renal artery of a rabbit inhibits norepinephrine overflow caused by stimulation of renal nerves.52 Such an effect could contribute to the increased vascular resistance produced by NSAIDs.

Existing evidence of interactions between NSAIDs and antihypertensives: clinical trials, meta-analysis, and observational studies

Clinical trials

Diuretics

There are a wealth of human studies that have examined the interaction between NSAIDs and diuretics.13-20, 50, 53-54 NSAIDs generally interact with diuretics by reducing their prostaglandin-related natriuretic activity.45 Such an inhibition can then result in increased body weight and attenuation of antihypertensive effects.14-15, 19-20 Altering the natriuretic activity of diuretics, however, does not completely account for the effects of NSAIDs. NSAIDs are able to inhibit the elevation of plasma renin activity of diuretics and hyporeninemic hypoaldosteronism has been shown in study subjects after the addition of NSAIDs to diuretics.14-16, 45 This effect could explain the increase in plasma potassium observed with the use of NSAIDs.

The effects of NSAIDs on suppressing natriuresis and plasma renin activity are not consistent among different drug categories.14-16, 45 Controversial findings have been observed with indomethacin and ibuprofen, as well as indomethacin and sulindac. In some studies, sulindac may even enhance the hypotensive effect of thiazides or leave it unaffected.14, 45 This may be related to the inability of sulindac to inhibit the renal synthesis of prostaglandins.45

b-blockers

Numerous studies have documented a blunting of antihypertensive effects of b-blockers by NSAIDs.13, 20-22, 51, 54-58 Two mechanisms have been proposed to be involved in such an interaction. 20, 22, 45 Increased circulating prostaglandins may play a role in the hypotensive actions of b -blockers. In addition, b-blockers can reduce plasma renin activity. Coadministration of NSAIDs therefore can attenuate vasodilatory prostaglandin synthesis and limit the antihypertensive component related to plasma renin lowering.45 Blunting of the antihypertensive effects of b-blockers by NSAIDs, however, were not universally seen.21,58-59 The difference in some of the results could probably be explained by the fact that inhibition of prostaglandins might lead to increased sensitivity of adrenergic receptor.45 Enhancement of b-mediated vascular tone by NSAIDs could then be more apparent in the presence of a nonselective b-blocker than in the presence of a highly selective one.

Vasodilators

Hydralazine, a direct vasodilator has been shown to enhance the synthesis of prostaglandins.38, 45, 60 Few papers, however, have studied the interaction between NSAIDs and direct vasodilators. Most of these studies failed to show any significant changes in the hypotensive effects of vasodilators, although some studies did reveal the attenuation of hypotensive effects of hydralazine by NSAIDs.26-27, 45, 61

Angiotensin-converting enzyme inhibitors (ACEIs)

ACEIs block the synthesis of angiotensin II and decrease the production of aldosterone. In addition. In addition, ACEIs lead to increased bradykinin level which promotes the release of prostaglandins.48 Several studies have then investigated the interaction between ACEIs and NSAIDs.23, 25, 28, 50, 62-66 Most studies demonstrated that ACEIs lowered blood pressure and caused a significant increase in plasma renin activity and urinary prostaglandin excretion, changes that could be reversed by indomethacin, but not (or minimally) by sulindac. In one study, for example, the combination of enalapril and indomethacin in hypertensive patients was shown to increase mean arterial pressure by about 5.5mmHg.62 It is noteworthy that the interference of NSAIDs on the hypotensive effects of ACEIs was most marked in patients with low-renin activity.44, 63-64

Calcium channel blockers

Calcium channel blockers relax vascular smooth muscle by blocking inward movement of calcium ions. Calcium antagonists can also induce natriuresis and diuresis, which may contribute to their hypotensive activity.67-68 In normotensive and hypertensive subjects, there were no changes in the hypotensive effects of calcium antagonists when coadministered with aspirin or indomethacin.23-24, 58, 69 In a study of hypertensive patients taking nifedipine, plasma renin activity, and urinary prostaglandin excretion were significantly reduced after the administration of indomethacin, while the hypotensive action of nifedipine was not affected.69 In another study of hypertensive subjects, plasma prostaglandin E2 level, and 24 hour urinary sodium excretion were significantly decreased after treatment with indomethacin, but plasma renin activity did not change.23

Peripheral a-1 blockers

Prazosin has been shown to enhance the synthesis of PGI2 and PGE2.38 NSAIDs may then attenuate the vasodilatory effect of peripheral a-1 agonist. Although in an 8-hour study, indomethacin was found to blunt the hypotensive effect action of prazosin in normotensive volunteers,70 clinical trials reporting the interaction between NSAIDs and a-1 blockers are lacking.45

Centrally acting agents

Animal studies have shown that clonidine may increase prostaglandin synthesis in heart, brain, and kidney of rats, and a variety of NSAIDs can blunt the hypotensive effects of guanfacine.45 However, no clinical trials have been conducted to examine the interaction between NSAID and central a-2 agonist. Similarly, no clinical trials have investigated the effects of NSAIDs on other centrally acting agents.

Meta-analysis

Since the results of small clinical trials are somewhat controversial, meta-analyses have been reported in an attempt to obtain better estimate of the overall effects of NSAIDs on blood pressure.71-72 In the first meta-analysis, Pope et al. evaluated intervention studies reported before 1989 which met the following criteria: (1) NSAIDs at any dose or aspirin at doses of 1.5g/day or greater; (2) treatment for at least 24 hours; and (3) documentation of blood pressure was provided.71 Totally, 54 studies with 123 NSAID treatment arms (n = 1,324, mean age 46 years) fulfilled the criteria. Among these, 65 trials arms were for indomethacin and 26 were for sulindac. The majority (1,213 subjects, 92%) of the 1,324 study subjects were hypertensive. Patients with severe hypertension or severe renal insufficiency were not included in these trials, and all trials were of short duration (all less than 6 weeks, and 50% < 2 weeks). In 84% of those trial arms, a normal salt diet was given, in 11% the participants received salt-restricted diets, and in 6% they were salt loaded.

In this study, Pope et al. found that normotensive subjects experienced only minimal increase in mean arterial blood pressure (MAP, 1.12mmHg on average), while hypertensive patients had more increment of blood pressure (3.32mmHg). The average increases in MAP were greatest for naproxen (6.1mmHg), indomethacin (4.77mmHg), and piroxicam (2.86mmHg). After adjustment for salt-intake level, however, the average change in MAP was significant only for naproxen (3.74 &plusmn; 1.90mmHg) and indomethacin (3.59 &plusmn; 1.12mmHg). Piroxicam increased MAP by 0.49 &plusmn; 3.46mmHg, whereas sulindac (-0.16 &plusmn; 1.45mmHg), aspirin (-1.76 &plusmn; 2.04mmHg), ibuprofen (-0.83 &plusmn; 2.40mmHg) and placebo (-2.59 &plusmn; 1.78mmHg) all produced decreases in MAP. When comparing the effects of various NSAIDs, indomethacin and naproxen were significantly different from sulindac and aspirin.

Pope et al. also investigated the interaction of NSAIDs and antihypertensives according to the initial MAP in hypertensive treatment subjects and variation of doses for each NSAID. No significant correlation was found between the change in MAP and these two variables. In testing for heterogeneity of change in MAP for data from different trials, Pope et al., however, found significant heterogeneity of changes in blood pressure among the indomethacin and ibuprofen trial arms.

In another meta-analysis reported by Johnson et al., 50 clinical trials (771 subjects, mean age 47.6 &plusmn; 2.5 years), published before 1990 and fulfilled their entry criteria, were reanalyzed.72 Among these, 38 trials included randomized and controlled trials, while 12 trials were randomized but using no placebo-controlled studies. Although nine NSAIDs were included in this meta-analysis, indomethacin was administered in more than half of all trials. Only 9% of the trials included blacks in their study cohort. Moreover, the diet was either unrestricted or not specified in most trials, which consequently limited the analysis of the confounding effect by salt intake.

In this meta-analysis, NSAIDs elevated supine MAP by 5.0mmHg (95% C.I. 1.2 to 8.7mmHg), but without significant changes in body weight, daily urinary sodium output, creatinine clearance, plasma renin activity, or 24-hour urinary prostaglandin excretion. When the randomized, placebo-controlled trials were classified according to population type, NSAIDs increased MAP in all subgroups. However, only those trials involving controlled hypertensive subjects showed statistical significance with pooling (mean increase 5.4mmHg, 95% C.I. 1.2 to 9.6mmHg). Those studies in which antihypertensive therapy was given were associated with a higher increase in blood pressure after NSAID treatment than those trials in which no antihypertensive drugs were administered (4.7 compared with 1.8mmHg, respectively).

Among those randomized placebo-controlled trials, NSAIDs antagonized the effect of all drug categories. NSAIDs produced a substantially greater increment in supine MAP when b-blockers and vasodilators (including calcium channel blockers, ACE inhibitors) were given, compared with diuretics. However, the pooled antagonistic effect of NSAIDs on blood pressure was statistically significant only in trials in which b-blockers were coadministered with NSAIDs (mean increase 6.2mmHg, 95% C.I. 1.0 to 11.4mmHg).

When analysis of randomized placebo-controlled trials was performed according to NSAID type, all NSAIDs increased supine MAP with piroxicam, indomethacin, and ibuprofen producing the greatest increases. Nevertheless, only piroxicam showed a statistically significant effect (6.2mmHg, 95% C.I. 0.8 to 11.5mmHg). Aspirin, sulindac, and flurbiprofen caused the smallest elevation in MAP, although 95% C.I. for the latter two were wide. Analysis of trials without a placebo group did not show any statistically significant elevation on MAP between comparisons of various NSAIDs, although indomethacin produced greater increase in weighted mean MAP than sulindac (6.0mmHg, 95% C.I. -7.7 to 19.7mmHg) and salicylate (5.7mmHg, 95% C.I. -34.7 to 46.1mmHg).

Large observational studies

In an Australian community-based study of 2,805 non-institutionalized residents aged 60 years and older, Johnson et al. found that NSAID use significantly predicted the presence of hypertension (odds ratio 1.4, 95% C.I. 1.1-1.7), even after adjusting for known confounders, such as age, sex, body mass index, prevalent coronary heart disease, smoking, and current alcohol. 7 The attributable risk percent estimates of NSAID use causing hypertension in this study were 28.6%. Current NSAID usage, however, did not significantly predict blood pressure in subjects not using antihypertensive drugs. Due to insufficient sample sizes of individual NSAID type, the effects of different NSAIDs were not analyzed.

Chrischilles and Wallace, in the Iowa 65+ Rural Healthy Study, examined the usage of NSAID in some 3,097 subjects.29 NSAID users were then identified and were frequency matched to subjects not taking NSAID on gender, age, five-year age group, body mass index, and current use of antihypertensive drugs. Although not statistically significant, among those taking antihypertensives, NSAID users were found to have mean systolic blood pressure about 5mmHg higher than nonusers of NSAIDs (4.86mmHg, 95% C.I. -0.02 to 9.74mmHg). NSAID users were also more likely to have systolic blood pressure above 140mmHg (odds ratio 2.19, 95% C.I. 1.33 to 3.61mmHg). Interestingly, among subjects not taking antihypertensives, NSAID users had lower systolic and diastolic blood pressure than nonusers (-1.34mmHg, 95% C.I. -6.67 to 3.98mmHg; -3.34mmHg, 95% C.I. -6.45 to 0.23mmHg, respectively).

Gurwitz et al. evaluated the risk of initiating antihypertensive treatment in elderly individuals in a case-control study.30 Among Medicaid enrollees aged 65 years and older, 9,411 patients newly started on an antihypertensive medication, and 9,629 controls without filling a prescription for an antihypertensive medication on or before a randomly assigned index date, were selected. After controlling for potential confounders, recent NSAID users (subjects whose NSAID supply continued into the 60-day period before the index date) were noted to have a significantly higher risk (odds ratio 1.66, 95% C.I. 1.54 to 1.80) for the initiation of antihypertensive therapy than nonusers. A dose-response relationship was also observed. The adjusted odds ratio for users of low daily doses relative to nonusers was 1.55 (95% C.I. 1.38 to 1.74), that for medium-dose users was 1.64 (95% C.I. 1.44 to 1.87), and that for high-dose users was 1.82 (95% C.I. 1.62 to 2.05). Risk of initiating antihypertensive therapy was greatest for those with duration of NSAID use of 30 to 90 days. Gurwitz et al. also calculated the nearly 10% of newly treated hypertensive cases would be attributable to the use of NSAIDs.

Interaction between COX-2 selective NSAIDs and antihypertensives

In recent years, two isoforms of the COX enzyme, COX-1 and COX-2, have been isolated.73 It is now clear that COX-1 is the constitutive form of the enzyme, present in gastric mucosa, the vascular endothelium, and platelet, and is responsible for the damaging side effects, e.g. gastrointestinal (GI) bleeding, ulceration, and renal insufficiency, following the administration of "conventional" NSAIDs.74-78 In contrast, COX-2 is mainly induced at the site of inflammation and is believed to exert the anti-inflammatory, and analgesic effects of NSAIDs.79-80 COX-2 isoenzyme, however, may still be present in normal human kidney, and vascular endothelia and smooth muscle cells.75, 81-82 In clinical trials comparing more COX-2 selective NSAIDs, such as meloxicam, nimesulide, and etodolac, with non-selective NSAIDs, it has been shown that COX-2 selective NSAIDs cause less, but not completely devoid of, GI and renal side effects than conventional NSAIDs.77, 80, 83 Their effects on blood pressure control, however, are not clear. No clinical trials have ever been conducted to investigate the possible interaction between these new NSAIDs and antihypertensive drug therapy. In addition, blood pressure change was not specifically measured in clinical trials evaluating the efficacy of COX-2 selective NSAIDs. Although these newer NSAIDs may theoretically have fewer or minimal interaction with antihypertensives due to their higher COX-2 selectivity, further clinical trials are needed to clarify this issue.

Clinical impacts of NSAID-antihypertensive interaction

Hypertension is a major determinant of the risk of stroke and coronary artery disease.84 A mean difference of 5 to 6mmHg in diastolic blood pressure over a few years may be associated with a 42% less stroke and a 14% less coronary heart disease events.84 The occurrence of the latter may be higher if the difference in diastolic blood pressure maintained longer.85 Suppose that NSAID therapy do cause prolonged blood pressure elevation, the clinical impacts of such drug interactions would be tremendous, given that 12 to 15% of elderly patients take these two agents concomitantly.5, 7 It has been estimated that in elderly patients treated with NSAIDs, about 30% of the hypertension can be attributed to use of these drugs.7 The higher incidence of drug interactions, low renin activity, and the multitude of medical illnesses in the elderly population could further increase the extent and severity of this problem.7, 86

The results from both meta-analyses suggested that NSAIDs can increase mean arterial blood pressure by about 5mmHg in treated hypertensive patients.71-72 Similar effects can also be observed in certain normotensive subjects. Although the long-term hypertensive effects of NSAIDs remain unknown, a significantly higher occurrence of stroke and coronary heart diseases might be anticipated in patients suffering such drug interaction - if this hypertensive action does persist over time. It then appears obviously that the use of NSAIDs in susceptible patients should be carefully evaluated and periodic monitoring of blood pressure is warranted in these patients.

Unresolved issues

Numerous clinical trials have clearly shown the hypertensive effects of various NSAIDs on blood pressure control.71-72 However, several issues remain unresolved. Firstly, the precise pathogenic mechanisms of NSAIDs are still not clear, although inhibition of prostaglandin synthesis appears to be one of the major pathway.5, 31-32, 87 Secondly, the differences in the extent of NSAID-antihypertensive interactions remain not well defined as conflicting data occasionally appear in the literature.71-72, 87 Data concerning the interaction between NSAIDs and certain antihypertensives (centrally acting agents, vasodilators) or antihypertensives and newer selective NSAIDs are also incomplete or totally lacking. Although meta-analyses have provided a better estimate of these effects and variation in the metabolism for each individual NSAID in different population may predict these differences, further studies are apparently warranted.87 Thirdly, the long-term effects of NSAID-induced hypertension in the elderly or other at-risk population are not well studied. Previous clinical trials were largely of short duration and most of them involved only younger and healthier population.71-72 Observational epidemiologic studies did evaluate the interactions between NSAIDs and antihypertensive treatment in the elderly.7, 29-30 Nevertheless, the long-term effects of NSAIDs on blood pressure control, coronary heart diseases, and stroke, and the varying toxicity of individual NSAID type have not been clarified. Moreover, the detrimental effects of NSAIDs on chronic debilitated patients who would be especially susceptible to drug-drug or drug-disease interactions are unknown.

Conclusions

NSAIDs and antihypertensive drugs are both commonly prescribed in clinical practice. Concomitant use of these two agents have been shown to produce a significant drug interaction with a 5 to 6mmHg increase in blood pressure. Since higher blood pressure can predict the occurrence of stroke and coronary heart diseases, critical and direct evaluation of the increased risks of these diseases in patients taking both drugs is definitely warranted. Although our knowledge of this important drug-drug interaction is still complicated by the many drug categories in both groups of drugs, there is an urgent need for more clinical trials involving large number of patients, combining more classes of both agents, and extending over prolonged periods. Large observational studies to investigate the long-term, varying cardiovascular effects of NSAIDs in the elderly and in those debilitated patients would also be important. Until more study results are available, however, the use of NSAIDs should be cautious in hypertensive or elderly patients. Early identification of high-risk patients should be considered, and frequent monitoring of blood pressure should be arranged. Replacement of conventional NSAIDs by newer COX-2 selective NSAIDs in patients with arthritis may also be recommended.

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