In the current study, patients receiving NSAIDs showed a 2 mmHg increase in systolic blood pressure compared to acetaminophen recipients. The systolic blood pressure increase was 3 mmHg in a sub-sample of those who were concomitantly prescribed ACE-I or CCB and 6 mmHg in those prescribed a beta-adrenergic blocker. Ibuprofen was associated with a systolic blood pressure increase, compared to both naproxen and celecoxib, of 3 and 5 mmHg, respectively. Despite these effects we did not detect significant changes in antihypertensive therapy in the NSAIDs users suggesting clinicians were not noticing these blood pressure changes that were admittedly subtle though sufficient to increase risk.
Similar to the current results, previous studies reported an up to 7 mmHg increase in blood pressure in patients who were stable on beta-adrenergic antagonists and had started NSAID therapy
[34, 35]. Interestingly, in our study the blood pressure increase associated with NSAIDs was greatest in patients prescribed a beta-adrenergic antagonist compared to other antihypertensive medications. The reason for this variation in blood pressure among antihypertensives could be related to the degree of prostaglandin (PGs) inhibition and the differences among these medications in their antihypertensive mechanisms. A proposed mechanism to explain this effect with beta-adrenergic antagonists is that inhibition of PGs by NSAIDs could increase sensitivity to the vasoconstrictor effects of sympathetic nervous system stimulation. Blocking beta receptors increases this sensitivity to the alpha sympathetic nervous system, resulting in abolishment of the blood pressure lowering effect of beta-adrenergic antagonists
. Further, some beta-adrenergic antagonists reduce the glomerular filtration rate
. In the long-term, this could increase the sensitivity to blood pressure increases by NSAIDs. This effect has important implications for those patients with heart failure and hypertension who have been prescribed beta-adrenergic antagonists.
The blood pressure increase we observed with NSAIDs in ACE-I users agrees with previous studies that reported a 5 to 10 mmHg increase in systolic blood pressure
[13, 18, 19, 23]. The inhibition of PGs by NSAIDs is proposed as the mechanism that explains the loss of the blood pressure lowering effect of ACE-I. Because PGs mediate the antihypertensive effect of ACE-I at least in part, inhibition of PGs by NSAIDs could disrupt the blood pressure control achieved by ACE-I
[19, 22, 38]. These observations may be particularly important in patients with diabetes. Antihypertensive treatment is often intensified in patients with diabetes mellitus
; in addition, patients with diabetes mellitus who are diagnosed with hypertension are more likely to receive an ACE-I rather than other antihypertensive medications to preserve renal function. Therefore, it is important to monitor blood pressure closely in diabetic patients who are prescribed NSAIDs to ensure adequate blood pressure control.
No statistically significant changes in systolic blood pressure were associated with a prescription for NSAID in patients who were prescribed multiple antihypertensive medications. This can be explained by small sample size in some of these combinations. Because some of the combinations with beta-adrenergic blockers involved only small number of patients, it is possible that this study was not powered to detect small effects.
Similar to previous studies
[10, 11], the current study found no effect of NSAIDs on blood pressure in patients who were using diuretics. Current hypertension guidelines recommend starting patients on thiazide diuretics because they are associated with better clinical outcomes and lower mortality rates than other antihypertensive medications
. In addition, diuretics are often less expensive than other antihypertensive medications. The absence of an effect of NSAIDs is further reinforcement for use of diuretics to control blood pressure in patients who were using NSAIDs.
The results of the current study may have some clinical implications. Blood pressure is often poorly controlled in hypertensive patients
, Our results raise the prospect that NSAID use contributes to that poor control found in numerous epidemiologic surveys. It is possible that more attention to the effects of NSAIDs on maintaining or achieving blood pressure control could lower morbidity and mortality and in so doing reduce health care costs
. For example, it was estimated that in the United States achieving or maintaining blood pressure control in users of selective COX-2 inhibitors would prevent more than 70,000 deaths from stroke and 60,000 others from coronary heart disease; such control would also result in direct health care cost savings of more than 3.8 billion dollars
. The small increase in systolic blood pressure associated with NSAIDs seen in this study may not affect a physician’s decision to change antihypertensive therapy. However, in the long-term, such an increase could be associated with significant comorbidity consequences. For example, decreasing systolic blood pressure by just 2 mmHg lowers stroke mortality by 10% and ischemic heart disease mortality by 7%
. Future studies are needed to assess the long term effect of such small increase in blood pressure.
This study has limitations that should be considered when interpreting the results. Patients included in this study came from a single health system and may not be representative of other practices. Hence, this study should be replicated in other clinical settings. Although propensity score matching balances many covariates at baseline, unobserved covariates could still differ between the groups. Bias is a threat to the validity of these results especially when comparing NSAID and acetaminophen groups. Acetaminophen has mild pressor effects that may have dampened the relative effects of NSAID
. Nonetheless, acetaminophen is often used as an alternative to NSAIDs and we therefore believed it was a reasonable non-NSAID comparator. Finally, several NSAIDs are available over the counter (OTC) as well as by prescription and this database captures only the use of prescription NSAIDs. However, because patients included in this study were provided with needed OTC NSAIDs through a prescription assistance program, it is less likely that they would have purchased additional OTC NSAIDs. Furthermore, sensitivity analysis research suggests that missing OTC drug exposure is not a significant source of bias
In conclusion, compared to acetaminophen, incident use of NSAIDs (particularly ibuprofen) is associated with a small increase in systolic blood pressure in hypertensive patients. Effects in patients prescribed diuretics or multiple antihypertensives are negligible.