Clinical and prognostic significance of serum magnesium concentration in patients with severe chronic congestive heart failure: The Promise Study

Clinical and Prognostic Significance of Serum Magnesium

Concentration in Patients With Severe Chronic Congestive Heart Failure: The PROMISE Study ERIC

J. EICHHORN,

GERALD

C. TIMMIS,

MILTON

PACKER,

MD,

FACC,

MD, MD,

FACCS

FACC,!

P. K. TANDON, PAUL

PHD,*

E. FENSTER,

ROBERT MD,

ON BEHALF OF THE PROMISE

DrBIANCO,

FACC,$

JAMES

MD,

FACC,t

SHANNON,

MD,11

STUDY INVESTIGATORS

AND COOHDINATORS~

06~ecrives. The aim of this study wus tu determine tbe prognustic significance of alterations in serum magn&uu in patients with moderate to severe ceugestive heart failure. Background.Reductions iu serum magnesium have been p++ tub&d to play a role in promoting arrhythmias and to have en adverse impact on survival in cougeltive heart failure, although support for this postulate is lacking. Merheds. Serum magnesium levels were measured in 1,068 patieutsenrolled in o survival study of class III or IV heart failure at the time of double.bliud randomizntion to mibinoue, P phosphodieslersse inhibitor, or placebo. All palien& received conventional therapy with digoxin, diuretic drugs and a converting enzyme inhibitnr throughout the trial. The median follaw.up period was 6.1 months (range 1 day to 20 months). Results. Patients with high serum magnesium [defined et ~1.9 mEqfiiter, n = 242) were less likely tu survive than were pa. tients with o n~rnud magnerium level (n = 627) (p < 0.05, risk ratio = 1.41). Patients with a low magnesium level (deRned os 11.5 mE&er, u = 199) had qu diiereuce in survival emupared

with the group with P normal magnesium level (p = NS, risk ratio = 0.89). At baseline, the patients in the bieh magnesium group were older and had mere severe functioual and renal impalrmeut. An analysis nftcr adjustment for these variables demonstrated WJdifference in survival compnfingthe low, normal and biib magnesium groups. Although the three groups had uo difference in frequency of ventricular tachycardis, length of longest nut or frequency uf veutriculor premetun beats on baseline Halter monitoring, the group with hymmie bad mure frequent veutriculpr couplets. Conclusions. Serum magnesium does not appear to be an independent risk foreither sudden deothordeatbdue toot1 cautes in patio&s with moderate to severe heert Failure. Hypemagnesetnin is awciated with an iacrew in the frequency of certain forms of ventricular cctepic activity, but this is uat associatedwith en inerase in ctiuicol events. The highs murtatity rste amoug the patltnts with hyprrmngnesemin L attrthutat& to Older ege, more advanced heart failure and renal i~illrkucy. (.I Am Cell Cur&al 1993$V!634-40)

Previously published studies (1.2) have demonstrated a high mortality rate in patients with congestive heart failure. As many as 30% 10 50% of the deaths associared with heart

failure car, be attributed to sudden cardiac death (1,3). The risk of sudden death appears to be present for all patients with heart failure. and ambulatory electrocardiography. programmed elecrrical stimulation and ventricular function assessment cannot reliably predict who will die suddenly (41. Although elevalions in some neurohormones such as plasma norepinephrine (5.6) and renin-angiotensin (as manifesred by hyponatremia) (5.7) have been associated with increased mortaliry rate in heart failure, the &logic factors responaible for sudden cardiac death are not understood. MagneGm deplelion may play a role in Ihe genesis of venlricular rhythm disturbances and could be an etiulogic factor in sudden death in patients with congestive heart failure (8,9). A xcent study (9) of 199 patients with congestive heart failure demonstrated that hypomagnesemia and hypermagczsemis were associated with a worse prognosis than that of a uurmal serum magnesium level. The patients with hypomagnesemiz had au increase in ventricular ectopic

From the Universrly of Texas Sou~hwcslcm 2nd Dallas VeteransAdminiswation Wediwt Ccntcrr. Dallar. l’exaa: “Aslra Pharmaceutical Products. W&wo. Massachuretla; Grdiology Research. Washington Adventist Hospital. Takama Park, Maryland; 4William Beaumont Hospital. Royal Oak. Michigan; Kardiolagy Se&n. Univcrrity Medical Ceaer. Tucson. Arizona: (Sterling-Winthrop Rcsuxh Institutr. M4vom. Pennsylvania and TDividon of Circulatory Phyaudugy. Collqe oi Physic&m and Surgeons of Columbia University. New York. New York. *A complete last of [kc PKOMtSE Study lnverti!glors and Coordinatan appears in Reference IO. This study was suppan by a gram from Slsrling-Winlhrop Pharmaceut~csts, Chesterbrook. Pemylvania Manuscript received May 27. 1992: revised manuscript recwed luly 27. ,992. accepted Augur, 20. ,992. m: Eric I. Eichhom. MD. Cardiac Cathelerizalion Laboratory llllA21.Univertily of Texas Southwesternand CJas Veterans AdminlYmtion Medical Centrrr. 4500 S. Lancaster. Dallas. Texas 75216. 01993 hy the American Coltcpc of Cxdmtugy

factor

0735.1097/43156.(1(1

events on ambulatory elcctrocardiographlc (ECG) monitoring and an increase in sudden cardiac death. Patients with hypermagnesemia had an increase in deaths due to progressive heart failure. These data suggested that magnesium may be a predictor of survival. The Prospective Randomized Milrinone Survival Eva$ation (PROMISE) (10) was a double-blind. placebocontrolled, prospective study of the sfYcf;;i if milrinone, a phosphodiesterase inhibitor. on survival in patients with heart failure and New York Heart Association functional class 111and IV symptoms. We examined the effect of serum magnesium at the time of study randomization on survival. Our hypothesis was that hypomagnescmia and hypcrmag nesemia would be independent risk factors fcr survival in patients with zevere heart failure.

Methods Between January 24. lY89 and October 41 1YYO. 1.088 oatients wirh functional class III or IV svmotoms and advanced left ventricular dysfunclion were enrolled in the PROMISE trial at 119 participating centers in the United States and Canada. The details of the study design have been published previously (IO). All patients had a left ventricular ejection fraction ~0.35 as assessed by radionuclide vcntriculagtaphy and had been receiving treatment with digonin. diuretic drugs, and a converting enzyme inhibitor for ~4 weeks. Treatment with nitrates, hydnlnzine. prruosin and other vasodilatorr was allowed. but beta-adrenergic blocking agents, calcium channel blockers, disopyramide. Recainide and encainide were excluded. Patients were excluded if they had obstructive vaivular disease. active myocnrditis. hypertrophic cardiomyopathy, amyloh! hean disease, uncorrected thyroid disease, prosthetic valvular disease or evidence of other systemic illness. Patients were also excluded if they had a history of seriorls symptomatic ventricular arrhytir&s, resuscilation from sudden death or ventricular fibrillation not wi!hin 24 h of a myocardial infarclion. Orhcr exclusions included severe and limiting angina pectoris. myocardial infarction within 3 months. systolic blood pressure
, ,

the diacrelion of the investigator. The cause of death (sudden death. myocardial infarction, progressive pump failure and w on) was reviewed in blinded fashion by the Motiity Committee of Ihe PROMISE tria: and classified as sudden or nonsudden. Sudden death was defined as an unexpected circ&tory collapse in a clinically sable patient (3,9). Statistical

analysis. Patients

were clasdimi

into three

group5 an the basis of their serutn ntrqnasium concentration

ilow. normal or high). This division wasdone retrospectively after comptetton of the trial. The low magnesium group was defined as having a level ~1.5 mEqlliter and the high magnesium group was defined as having a level ~1.9 mEq! liter. These definitions were based on the dislribulion of magnerium levels in the coholt as a whole. with approximately 10’3 of the patients having a low magnesium level, 20% a high magnesium level and 60% a normal magnesium level. Ott: definition ofhypomagnesemia (~1.5 mEqfliter) is more extreme than that of a prior report (9) that demonstrated worse survival in patients with low serum magnesium. Cumulative survival curves for the three magnesium groups were constructed by Kaplan-Meier survivorship methods and the differences between the survival curves were tested for significance by Mantel-Cox log-tank methods (I?). Survival curves for all cause mortality, sudden death and nonsudden death were examined for all three magnesium groups. Differences in baseline characteristics among the patients in the three groups were analyzed by an analysis of variance followed by muhiple comparison lests (Newman-Keulsrestl. For a few comparisons, a Mann-Whitney nonparametric test was employed when the distribution assumptions were not met. The three groups were again analyzed by Kaplan-Meler survivorship. correcting for the baseline differences in functional class. renal function and age among the groups. A similar analysis was performed on the subset of patients randomized to milrinone and the subsrt of patients randomized to placebo to determine whether an interaction of milrinonr and magnesium existed. All results are expressed as mean value f I SD unless otherwise specified. A p value < 0.05 was used to define statistical significance.

(II)

Results Serum magnesium was collecLed and recorded in 1,068 of 1.088 patients randomized in the trial. The strum magnesium concentration ranged from 0.3 to 3.3 mEq/liter. From the cohort of l.C!JJ oatients. I99 Datients (19%) had a low magnesium level, 627 (59%) had a normal range magnesium level and 242 (22%) had a high magnesium level. As serum magnesium was measured in each individual institution, some variation in technique and reproducibilhy among lab oratories exists. Mortality iales in the Imv, normal and hi@ magnesium groups (Table 1). There were 286 deaths (26.8%) in the 1.068 patients randomized in the trial at 20 months of follow-up. There was an increase in all cause mortality in the lugh

magnesium group (p < 0.05 vs. the normal magnesium group, risk ratio = 1.41) and no difference in mortality in the low magnesium group comparedto the normal magnesium group (p = NS vs. the normal magnesium group, risk ratio = 0.89). There was no difference among the three groups with resnect to sudden death. Thus. the increase in mortalitv rate in the high magnesium group wns related to an increase in nonsudden death. There was a 19.8% incidence rate of nonsudden death in the high magnesium group compared with a rate of 13.2% and 13.1% in the normal and low magnesium magnesium

groups, group,

respectively risk ratio

(p -C 0.01

vs.

Table 2. Comparison of Baseline Characrenslics in Low. Normal and Hieh Maenesium Grouos Serum Mdylesium Level tmlaniw)

the normal

= 1.75). A majority of the nonsudden deaths were due to pump failure in all three magnesium groups; the high magnesium group had the highest incidenceof death due to progressive pump failure. Adjustment far differences in baseline charseterktics (Table 2). Differences in 21 baseline characteristics arc shown in Table 2. As is evident, compred with the normal magnesium group, the high magnesium group was slightly older (47 -C 9 vs. 63 * years), had worst renal function (blood urea nitrogen 40 i 23 vs. 27 ? I5 mg/dl and creatinine I .7 i 0.5 vs. I.4 5 0.4 meidl) and had worse heart failure as reflected by more pai& in functional class IV (54% vs. 3%) and had slightly lower diastolic and systolic blood pressures.Comparedwith t:ie normal magnesium group, the group with low magnesium was younger. had less ischemic heart disease and had fewer patients with a previous myocardial infarction. .4s expected, the low magnesium group had a lower serum potassium concentrdlion (p < 0.05). However. as hypokalemia (serum potassium G.5 mmoll liter) was an exclusion to randomization. serum potassium levels were corrected before entry into the study. Thus, serum potassium was net in swady state at entry into the trial and the survival curves were not adjusted for differen~es in this factor. To determine whether an elevated s’ urn magnesium level was an independent risk factor for cardiovascular death, the data were examined after adjuslmenl for baseline

1I

differences among the groups. Cox regression analysis was performed lu adjust for the foltowing vatiabies; btood urea nitrogen, diastolic blood pressure, functional class and percent with ischemic heart disease. After adjustment for these baseline differences. Cox regression analysis demonstrated

Ln = IWI

A@wr)

6ut 12*

(n = 627) 63 f II 7s ss 39 39 59 26 26 27 5b 52

fn = 2421 61 f. 9t 82 57 54t 49’ 58 25 23 28 62 s2

SUDDEN

no difference in all cause mortahty or nonsudden death previously present between the hiah versus normzd masncGum groups (p = NS. risk ratio = .03 for all cause tnor~~h~y and p = NS. risk ratio = Lllfor nonsudden deathi (Table I. Fig. I). No differences in sudden death (p = NS. risk ratio = 0.95) appeared between the high and normal magnwum groups. Nwtnal and low magncAon groups again showed IIU differences in either all cause mortality (p = NS, risk ratto = 0.98). sudden death (p = W, risk ratio = 0.83) UT nonsudden dwlh (p = NS. risk ratio = I. IO) (Table I. Fig. 2). IXecl of magnesium mncentration an survival in the placebo and milrinone graups. Survival curw were exmv ined separately for patients in the placebo and milrinone groups. The prognvatic value of magnesium was unaffected by the drug to which the petient was randomized and was Fonsistent across placebo and milrinone groups. No mtcraction of milrinone with magnesium levels was observed.

I

DEATH

E&t of magnesium concentration on venhirmlv ectapic activitr (Table 31. Table 3 shows the 24-h H&r results for thr I,M8 patients. There were no differences among the mwncrium~roups with regard to mean numbcrof premature vrnlricular heats/h, number of daily ventricular tachycardia events or length of longest runs. There was a larger number of pailed ventricular premature beats&y in the low magnevuin @cup (p < 0.05 YE. normal and high magnesium groups). Ventricular ccwplcts were not associated with incrcascd t&I. cudden or nonsudden mortality. Discussion The importance of serum magnrsium as a prognostic indicator of survival in patimts with congestive heart failure has been widely drbatcd (4.X.9,1~221). These data taken from a Langeprospective trial suggest that although elevated

Figure 2. Adjusred Kaplan-Meier survivorship curves showing all cause mortality. sudden death and nonsudden death and stratified on magnesium (MG) level al entry flow vs. normal magnesium leiel) are shown. The solid Ii& represent mtients wilh a normal maEncsium level; the dashed Ilnes, &enls with a low magn&m level. There wxe ne differences in survival between the low and normal magnesium groups after ddjuslmeat for differences in baseline characteristics.

serum magnesium correlates direcliy renal funclion and worse ventricular independent risk factor for sudden Additionally, hypomagnesemia does

with older age. worse function, il is not an or nonsudden death. not appear lo be a risk

Tabk 3, Halter Electrocardiographic Analysis of Patients With High. Normal and Lcw Magnesium Levels at Baschne Study Serum Magnesium (mEq:lalerl Holler ECC Finding Log PVCS PVC pairdday lmedianl Length of lunpsl run ,mcdianl VT evenrrldaylmcdirni

51.5

1.5-l 8

1.xt071 !Z 7. 3

I .61 e 0.x Ih

12

3 I

21.9 1.66 t 0.77 13 3 1

*p C 0.05 versus normal magnesium. PVC = Premature vemrlculal ectopic beats: VT = venlwular lachycardia.

factor for either sudden death or all cause mortality. Although previous studies (9) of magnesium have noted the association between hypermagnesemia and worse ventricular function, it has no1 been clear whether ventricular dysfunction completely accounred for this increase in mortality or w’bether magnesium played an independent role because adjustment for ventricular dysfunction was no1 performed. The reason for an association between hypermngnesemia and older age and more impaired renal and ventricular function is not clear from this study because we did not assess renal clearance of magnesium. However, in such parients, impaired renal blood flow and clearance may play a pivo!nl role in the generation of an increased serum magnesium. Theoretic 1’01eof magnesium in the genesis of arrhythmias. There are several reasons why magnesium has been thought to play a role in the genesis of sudden death in patients with

II

Magnesium may have 3 profotz+ effect on ion channels in the hean. Magnesium is an esscn~~al cofactor of adenosine xiphosphate IATP) for the generalion of contraction. Progressive increments in cytosolic magnesium may block inward calcium c~rrer~t (?2.13). reduce outward (slow) sodium transport (13.24) and modify action potential duration by an effect on potassium channels (13J.l ,X26). The change in cytosohc magnerium necessary to effect a change in lhese ion channels is very small and within the physiologic range for mammalian myocyles 131. However. to date snch changes have nor been documented in viva. 2) The prevalence of magnesium deficiency is high in congestive heart failure. ranging from 7% 10 379 (8.U. 27.28). In our study, 345 (32%) of patients had a serum magnesium level
congestive hezrr failure.

t

I.068

C

poor correlation exists between serwn magnesium and tissue

magnesium Il3.4.31). For this reason, oar meaSuremeat of sernm magneswm may have been poorty reflective of the concentra!ion of free cytosolic magnesium. Additionally. we measured serum magnesium at baseline entry into the study. Over the follow-up period, patients mq have crossed ovw from a low magnesium lo a high magnesium group or vice versa. depending on diuretic use. neurohormonal activation. nutrition and renal function. Previous reports (13) of rhythm disturbances due to hypomagnesemia have all been associated with hypokaiemia as an accompanying feature. Indeed. because the causes of hypomagnesemra and hypokalemiaare so similar. hypomag nc~cnw rxcly exi$ts without hypokalemia. Thus. it is di@ cult TO dinlinguish whether hypomagnesemin by itself produces clinicai rhythm disturbances. In addition. despite laborai+ry evidence of :h; c!ectrophysiologic effects of hypomagnczmia (16). isolated reductions in serum magnesium do not result in changes in the KG (13.40). These data raise questions as to the effect of magnesium on the produclion of rhythm dismrbances. Although hypomagnesemia has been shown in some scnes (in the presence of hypokalemia)

lo produce or exac-

crbatc rhythm disturbances. this does not necessarily 7rans-

late into an increased mortality rate. Previous trinln (4.411 have shown a lack of correlation between ambient ectopic activity and sudden death. Conversely. the ability of magnesium admimslrmion IO suppress rhythm disturbances does no, nccc>sarily nanslate imo improved survival. although several powmyocnrdial

infarction

trials (39.42-44)

are srrg-

gestive. However.

prolonged survival after myocardial inFarction rnav be due IO effects other than motection from rhythm disrurbances (44). Thus. extrapolation of such data to chronic hear1 failure may not be valid. In addition. an increase in serum magnesium from oral or intravenous supplementation may not necessarily translate inro increased free cyrosalic magnesium. Conclusion. Our study has demonstntcd

that ahemiions

in serum magnesium are not an independent risk factor for sudden death. However.

it is not clear whether magnesium suppiementarion might produce a survival benefit. Such a hypothesis merits fuflher investigation.

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magnesium. Thus, it is not surprising that a

5. Packerhl. L
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