Best Evidence Interview: CINODs — The NSAID Holy Grail?
Linda Brookes Good, MSc
A Best Evidence Interview With William White, MD
The Best Evidence Study
William B. White, MD, is the lead author of the following study:
White WB; Schnitzer TJ; Fleming R; et al. Effects of the cyclooxygenase inhibiting nitric oxide donator naproxcinod versus naproxen on systemic blood pressure in patients with osteoarthritis. Am J Cardiol. 2009;104):840-845.
This study was selected as the subject of this interview because of its high ranking in Medscape Best Evidence, which uses the McMaster Online Rating of Evidence System. Of a possible top score of 7, clinicians who used this system ranked this study as 6 for relevance and 7 for newsworthiness.
About the Interviewee: William White, MD
William B. White, MD, is Professor and Chief of the Division of Hypertension & Clinical Pharmacology, Pat and Jim Calhoun Cardiology Center, University of Connecticut School of Medicine, in Farmington. Dr. White is a fellow of the American College of Physicians, the Council for High Blood Pressure Research of the American Heart Association, and the International Society for Hypertension in Blacks, and a charter member of the American Society of Hypertension. He is also chair of the study section for the Catherine and Patrick Donaghue Medical Research Foundation in Hartford, Connecticut.
Dr. White has a long-standing interest in clinical hypertension and pharmacology, particularly in the areas of ambulatory blood pressure monitoring, clinical trials of antihypertensive drugs, and the impact of cyclooxygenase (COX)-2 inhibitors in cardiovascular disorders. He is the author or coauthor of over 300 articles and book chapters in the field of hypertension and clinical pharmacology. Dr. White’s recently published books include Blood Pressure Monitoring in Cardiovascular Medicine and Therapeutics and Hypertension and Related Disorders. He is editor in chief of the journal Blood Pressure Monitoring, and he serves on numerous other editorial boards, including the American Journal of Hypertension, American Journal of Cardiology, American Journal of Medicine, Clinical Pharmacology and Therapeutics, Ethnicity and Diseases, Journal of Human Hypertension, Journal of Clinical Hypertension, and Hypertension.
Introduction to the Interview
Nonsteroidal anti-inflammatory drugs (NSAIDs) are universally used in the treatment of conditions that cause chronic pain, such as osteoarthritis (OA). However, their use is limited by their safety profiles, particularly gastrointestinal side effects and adverse effects on the cardiovascular system. Traditional NSAIDs such as ibuprofen and naproxen, which act by blocking the COX-1 and -2 enzymes, and COX-2 selective inhibitors, such as celecoxib, are associated with the destabilization of blood pressure control. This effect is particularly marked in hypertensive patients treated with blockers of the renin-angiotensin system (RAS).
Naproxcinod, a nitric oxide (NO) derivative of naproxen, is an investigational drug and the first of a class of NSAIDs known as COX-inhibiting NO donors. It is being developed by NicOx S.A. (Sophia Antipolis, France). Naproxcinod has been studied in a clinical phase 3 program in patients with OA of the knee and hip, and, on the basis of the results of these studies, it is currently under regulatory review for approval for treatment of OA in the United States. As of the date of this interview, a regulatory submission is also planned in Europe for late 2009. In preclinical studies, naproxcinod had similar anti-inflammatory and analgesic activity to naproxen but caused less gastric injury. Phase 2 and 3 trials showed that naproxcinod is an effective analgesic agent with reduced gastrointestinal toxicity compared with naproxen, and in contrast to naproxen, it reduces systemic blood pressure by 2-3 mm Hg. On the basis of these findings, naproxcinod may represent an alternative to traditional NSAIDs or COX-2 inhibitors in patients who have or are at risk for cardiovascular disease.
In the best evidence study discussed in this interview, the effects of naproxcinod on blood pressure in patients with OA were compared with those of naproxen and placebo over 13 weeks in a phase 3, randomized clinical trial carried out at the University of Connecticut, Farmington, and Northwestern University, Chicago, Illinois. The results of the trial, which were first presented at US and European rheumatology and cardiology conferences,[1,2] were published recently in the American Journal of Cardiology.[3] The trial randomly assigned a total of 916 patients with OA, with or without a history of hypertension, to treatment twice daily with either naproxcinod 750 mg, naproxcinod 375 mg, naproxen 500 mg, or placebo. Reductions in systolic blood pressure (SBP) with naproxcinod 750 mg were larger and significantly different from those with naproxen 500 mg at 2, 6, and 13 weeks (P < .05). The difference in mean change from baseline between these 2 groups was -2.9 mm Hg (P = .015). The 2 doses of naproxcinod showed reductions from baseline in diastolic blood pressure relative to naproxen (P < .04) and similar changes compared with placebo. The proportion of patients in the overall population with SBP increases > 10 mm Hg was greater with naproxen 500 mg (22%) compared with naproxcinod 750 mg (14%; P = .04), naproxcinod 375 mg (14%; P = .055), and placebo (15.6%; P = .155).
Separate analysis of a subgroup of 207 patients with hypertension treated with RAS-blocking agents alone or with diuretics showed a difference in mean change from baseline in SBP between naproxen 500 mg and naproxcinod 750 mg of -6.5 mm Hg in favor of naproxcinod (P = .011). Analysis of 73 patients being treated with antihypertensive drugs that did not include a RAS blocker did not show any statistically significant differences from baseline in SBP within or between groups.
The study authors concluded that naproxcinod is likely to destabilize the control of SBP compared with naproxen in patients with OA and behaves in a similar fashion to placebo overall as well as in patients treated with antihypertensive therapies involving blockade of the RAS. They suggested that the hypertensive burden induced by traditional NSAIDs in patients with OA and hypertension could be reduced by an NO-donating agent such as naproxcinod.
Lead author William B. White, MD, spoke with Linda Brookes, MSc, for Medscape Cardiology, to discuss some of the implications of this study for Medscape’s readers.
The Interview
Medscape: This study was the first, large-scale randomized clinical trial to investigate whether naproxcinod caused blood pressure destabilization in patients with OA that used standardized blood pressure measurements. What had earlier studies with naproxcinod shown with respect to its effect on blood pressure?
Dr. White: The phase 1 and 2 studies were very small, mostly in patients with OA, but one looked at hypertensives without OA, and they demonstrated a definite difference in blood pressure effect between naproxcinod and naproxen.[4-8] The pharmacodynamics of that were related to the time of dose, ie, the biggest blood pressure difference between naproxcinod and naproxen occurred during the first 8 hours after the dose of naproxcinod or naproxen was administered. Subsequently, there was a study done that compared naproxcinod, ibuprofen, and naproxen with placebo, and in that study, ibuprofen caused the greatest increase in blood pressure, naproxen the second largest, and naproxcinod and placebo were basically neutral.[9] So, those data predicted what we were expecting to see in this much larger clinical trial.
Medscape: The trial included a majority (about 70%) of women, and the mean age was 61 years, with one third of the patients aged 65 years or older. Was this cohort typical of the population that presents with OA?
Dr. White: OA is a more common disorder in women. In OA clinical trials, sometimes 75% of the population is older women. Usually the mean age of participants in OA trials is in the late 60s.
Medscape: What is the prevalence of hypertension in patients with OA?
Dr. White: Most surveys show that about 40% of patients with OA are taking treatment for hypertension, but probably a higher percentage actually has hypertension. That is usually because in this age group, there is more systolic hypertension developing as arteries get stiffer, and there is the loss of estrogen that seems to have a vasodilating effect. Together, these increase the prevalence of hypertension. The prevalence of hypertension in the entire population is about 20%-25%, but it is much higher in the OA population due to age.
Medscape: Not all the patients in your study had hypertension.
Dr. White: No one was selected for whether he or she did or did not have hypertension, but about 50% of the population in the trial did have a medical diagnosis of hypertension and was treated with various antihypertensive drugs.
Medscape: Most (more than 90%) of the 457 hypertensive patients in the trial were being treated with some form of antihypertensive therapy. About 23% were taking RAS agents. This subgroup group was also analyzed separately; why was that?
Dr. White: There was a hypothesis that we generated before we did this analysis, on the basis of earlier work that I and others did, showing that patients who were taking a RAS-blocking drug, which could be an angiotensin converting-enzyme (ACE) inhibitor, an angiotensin receptor blocker (ARB), a renin inhibitor, or even a beta-blocker (which also inhibits renin release), either alone or in combination with a thiazide-type diuretic, could be more predisposed to destabilization of blood pressure by NSAIDs.[10-12] This effect could arise by 2 mechanisms. One is that NSAIDs enhance salt and water retention, increasing plasma volume of the body and, by doing so, mitigate the effectiveness of the other drugs. The same will happen if you eat a high-salt diet in the presence of an ACE inhibitor or an ARB. The other mechanism is related to the way in which ACE inhibitors lower blood pressure by increasing the amount of bradykinin in the circulation. Bradykinin, a weak vasodilator, works in part by stimulating prostacyclin production. So, taking a conventional NSAID that impairs the generation of prostacyclin and subsequent NO release will have an impact on the mechanism of action of an ACE inhibitor. I think, then, that it was probably that interplay that was responsible for the different responses in the treatment groups that we studied. We also looked at the hypertensive group that was being treated with non-RAS blocker therapy, but we did not see any statistical significant differences from baseline in SBP within or between groups in this small subset.
Medscape: Would the mechanism of action of naproxcinod that prevents blood pressure rise in normotensive patients be the same as that in hypertensive patients controlled on a RAS blocker?
Dr. White: I think that it is all part of the same thing. My general thought is that among the population at large with OA, if you take a large group, half of whom are normotensive and half are hypertensive, the more impressive effect will be seen in the hypertensive than in the normotensive individuals. That is, if you give a conventional NSAID, such as ibuprofen or naproxen, a fairly substantial minority of those patients, maybe 15%-30%, will have a further increase in blood pressure, but it will be much less in the normotensives than it would be in the treated hypertensive population because it is not very easy to make a normotensive hypertensive by causing salt and water retention unless he or she has underlying renal disease. So, there is a small increase, and that would be less likely to occur with the NO donation of naproxcinod. Then, in the hypertensive population, whether or not it is on a RAS blocker vs another agent, it is more likely to have a rise in blood pressure on a conventional NSAID than its normotensive counterpart. But again, NO donation seems to prevent that from happening. It does not necessarily lower its blood pressure compared with baseline, but it keeps it from rising any more than with a placebo. The population of treated hypertensives that is on RAS blockers has the biggest benefit in terms of the difference in blood pressure increases on a conventional NSAID vs the lack of increase on an NO donating drug like naproxcinod. So, I think that that we are going to get most of the clinical benefit in treated hypertensive patients on antihypertensive drugs like ACE inhibitors, ARBs, diuretics, and beta-blockers, which is actually almost all of them because sooner or later, hypertensive patients will end up on one of those classes of drugs.
Medscape: Presumably they are likely to be on combination therapy with at least 2 or more drugs of different classes; what effects would naproxcinod have on blood pressure in these patients with OA?
Dr. White: Patients with OA on combination antihypertensive treatment will be more complicated to treat because if a patient is on an ACE inhibitor and a calcium channel blocker, which is quite likely nowadays, we cannot be completely sure what the effect of a COX-inhibiting NO donor will be. There will be a heterogeneous impact of the NSAID on the one hand; in the ACE inhibitor situation, it is going to raise the pressure, but with the calcium channel blocker, it is going to have very little effect. So, that might actually attenuate to some extent the rise in blood pressure seen with an NSAID compared with an ACE inhibitor alone. But this has not been a very well-studied population, so we do not know very much about this.
Medscape: So, not much is known about the effects of even traditional NSAIDs in hypertensive patients on combination antihypertensive treatment?
Dr. White: No, we do not know very much about the traditional NSAIDs in the population taking combinations of antihypertensive drugs in general. However, I hope we will soon know a little more about patients taking combination antihypertensive drugs vs those taking an ACE inhibitor or an ARB alone because in the coming months, I will be looking at this in a very large database with naproxcinod that was prespecified in about 3000 patients from 3 large clinical trials. I would hope to present that analysis at US and European meetings and submit it for publication in 2010.
Medscape: Two doses of naproxcinod were evaluated in your study. Could you say something about the differences in effects seen with the 375 and the 750-mg doses?
Dr. White: A 375-mg dose of naproxcinod is equipotent to 250 mg of naproxen but with each molecule of naproxen having 1 NO molecule linked to it. When a patient takes 750 mg of naproxcinod, he or she is taking an equipotent dose of naproxen, which would be 500 mg, with 2 NO molecules linked. So, there is greater efficacy in treating OA with the 750-mg dose, and because there is more NO release for that dose, there is a larger change in blood pressure in the downward direction. So, naproxcinod 750 mg is more likely to not increase blood pressure relative to 375 mg. The 375-mg dose is not statistically different from placebo, but its effect on blood pressure numerically is about 1 mm Hg higher than the 750-mg dose.
Medscape: Five hundred milligrams of naproxen is the dose usually prescribed in OA?
Dr. White: Yes, very few patients take naproxen 250 mg twice a day for arthritis because it is not effective enough. I understand from my colleagues in rheumatology that 250 mg is used in more than 20% of all prescriptions for naproxen.
Medscape: One serious adverse cardiovascular event occurred with the 750-mg dose of naproxcinod in this trial, although this was in a patient who had cardiovascular disease at baseline. Is this consistent with other data?
Dr. White: There has been no increase in cardiovascular events seen in studies with naproxcinod, including the pooled data, although it should be kept in mind that the average duration of these studies was 13 weeks. However, the impact of relatively small increases in SBP on cardiac events in patients with hypertension and vascular disease has been demonstrated in a number of clinical trials. In addition, naproxen (as a molecule) has been studied in large clinical trials, and in contrast to other drugs — of course, we do not know against placebo, but at least against other NSAIDs — it looks to be better in terms of development of cardiovascular disease events. I would not consider those data definitive, but naproxen certainly looks better than ibuprofen and diclofenac, the other 2 widely used NSAIDs. So, most people in the cardiovascular community recognize naproxen as probably being the more cardiovascular friendly of the NSAIDs — not that it cannot increase blood pressure, and it can increase gastrointestinal events — but certainly it may not be prothrombotic because it has a long enough half-life and a long enough antiplatelet effect.
Medscape: Do you think that many physicians are aware of the hypertensive effects of NSAIDs?
Dr. White: I think that prescribing rheumatologists or internists usually know what other medications their patients are taking, but cardiologists know very little about NSAIDs, quite frankly. They may very often not recognize the fact that one of the mechanisms for hypertension is, in fact, the NSAID a patient is taking.
Medscape: So, do you think that cardiologists will eventually become more aware of this effect of NSAIDs? Maybe they need not be aware of it if patients are already taking a drug like naproxcinod, if that isn’t a too flippant way of looking at it?
Dr. White: I think from a public health perspective it is a good way of looking at it. Here is an NSAID that does not destabilize or increase the blood pressure, so it would have to have a greater potential for long-term safety in a population of treated hypertensives. That is a good thing. Whether that will ultimately translate into fewer strokes and development of less heart failure will, I think, require a registry study of some sort when it has become more widely available. You need to look at a population of hundreds or thousands to determine that rather than a clinical trial, which would not be feasible because it would be too expensive and too time consuming.
Medscape: Is there anything else that researchers should be looking at with naproxcinod in the meantime?
Dr. White: We should learn more about the effects of NO in the regional vasculature with this drug. For example, NO itself is vasoprotective; it improves renal blood flow and coronary blood flow. So, one of the questions we might ask is whether it might be safer to use this drug in populations that we might have avoided treating with NSAIDs until now, for instance, patients with mild renal dysfunction (stage II chronic kidney disease) or peripheral vascular disease. There should be a lot of interest in evaluating this further because those are populations who have arthritis, and they have pain, and yet they are currently denied these drugs because of that.
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