Getting to Goal Blood Pressure despite Disaster Capitalism: Why Reserpine Deserves a Second Look

 Lets hear your comments for or against  a return to evidence-based medicine for hypertension, not marketing  hype:

Last week this op-ed column discussed the time-bomb of obesity–  overnutrition, and the wannabe panacea designer drugs of the Disease Industry.

Instead of the narrow Disease-Industry driven multiple designer  prescriptions for hypertension, lipidemia, vascular, depression, dementing and musculoskeletal diseases, the patient – and  lowering the costs of major disease- are far better served by recommending the natural supplements and the old and well-proven few prescription drugs often justified- lowdose amiloretic, lowdose reserpine, metformin., and appropriate parenteral HRT.  

The problem is that Politicians, Treasury, doctor and medicines Regulators, Stock-markets, the Media, Academics and practitioners are all far more impressed by the billion-dollar buying and marketing persuasions of Big Pharma than the truth that is in patients’ (but not the Disease Industry’s) interests.

 

It took 20 years to defeat the FDA-Drug Industry in USA and have old metformin and lithium registered there- so that these are  now worldwide the core drug therapies for type 2 diabetes and bipolar disease respectively  in most  patients.

Until lowdose reserpine plus lowdose co-amiloretic are  similarly restored as the initial therapy of essential hypertension world wide, the growing epidemic of essential hypertension remains in Noam Chomsky’s terms a Failed State of medicine, one of the prime successes of Kissinger-Rumsfeld-Cheyney-Bush- FDA type for-profit subversion of democracy and evidence in therapeutics – and blow the Innocent Casualties


The  August 2007  review summarized below  Getting to Goal Blood Pressure: Why lowdose co-thiazide-reserpine remain the first tier therapy review (which spells out all the acronyms)  from Kaiser Permanente and University clinics in three States,  is  crucial to managing the hypertension epidemic.

 

It amplifies the primacy  of the lowdose reserpine- lowdose co-thiazide diuretic combination over all other drug combinations with new data from the MRFIT study as well as from  the VA, HDFP, SHEP and ALLHAT trials – noting that in low dose these drugs have zero adverse effects (compared to methyldopa, betablockers, ACEI, CCB and ARBs) but a good BP control rate.

 

No antihypertensive drug acts  smoothly and safely for 24hours ie once a day dose except resserpine- which acts for many days; and no antihypertensive drug on its own normalises bloodpressure in the mjority of patients with mild to moderate hypertension.. Thus the ideal primary therapy remains lowdose reserpine plus lowdose coamiloretic.

 

The compelling year-old US review by Barzilay ea  omits a couple of crucial facts/ updates:

 

1. In South Africa, reserpine is still registered,   and recommended by experts as a valuable second-line antihypertensive- but – as in UK and Europe – it has been dropped from the State Clinics’ formulary, for which the responsible authorities ( in  RSA, UK and EU)  blankly refuse to give any scientific reason, since there are none.

This leaves the responsible decision-makers, by default of any other reason, tacitly admitting they bow to the financial enticements  of the pharmaceutical industry who prefer to research and sell more modern ie patented costly blocker drugs and especially patented combinations of the latter- although such combinations have never been proven to be anywhere as good as the lowdose reserpine- lowdose diuretic combination.

 

eg the ASCOT  trial merely confirmed  what was known,  that  brisk diuretic plus a BBlocker is not the best choice for the population tested.    ASCOT was done not in the average new middle-age hypertensive  in a temperate climate,   but like WHI, ALLHAT & SHEP, in  a highrisk older Anglo-Scandian  population mean age  63 yrs living in a much colder climate, many obese (mean BMI 28,3kg), 1/3 smoking, 80% already on therapy, and 60% already with (micro)proteinuria.

   there was no mention of  a good practice control  group ie on effective (eg Ornish- or DPP or UKPDS type) non-drug management, nor a control group on lowdose thazide-reserpine.+- eg amlodipine/ACEI for proper BP control.

Thus there s no basis to say that  a (combination of)  ACEI/ARB/CCB  should be universal firstline therapy.  Even compared to a bad combo like vigorous thiazide + atenolol,  in ASCOT the results of  Secondary endpoint (nonfatal AMI  excl silent AMI, + fatal CHD) barely reached  statistical significance, let alone the failure to achieve the primary endpoint significance (nonfatal AMI + CHD); and allcause mortality did not achieve POEM significance ie  2%pa on ThiazAten vs 1.8%pa on PerinoprilAmlod. (Patient Orientated Evidence that Matters – Shaughnissy & Slater).

      Most major endpoints were predictable, were to be expected in that population:

inappropriate BBlckade caused more PVD, bradycadia, cough, dyspnoea, periph coldness; heartrate was 11bpm higher on the peri/amlo combo, despite serum K level only 0.05mmol higher.  Inappropriate highdose thiazide + BB caused more erectile dysfunction, renal impairmnt & new diabetes-   yet there was no difference in chronic angina, hear failure, lifethreatening arrhythmia.

Perindopril on the other hand predictably caused joint swelling in 14% (vs 3% on thiaz-atenol); and the diuretic-free combo  predictably caused  periph oedema in 23% (vs 6%).  It is salutory that the discontinuaton rate due to adverse reactions was identical 24.7% for the two different regimes – confirming that the new patented combination is no better than even the old thisazide- bblocker one.

2. as hypertension experts  Drs Norman Kaplan, Marvin Moser, Jos Barzilay et al from USA, and South African Hypertension Society’s  Drs YK Seedat, Harry Seftel, Willie Mollentz,  Mark Blockman  et al agree in personal discussion, and by WHO pharmacy expert Kirsten Myhr  2002  and Urquhart 2003,   on what scientific  basis  is lowdose reserpine  restricted, no longer in the first tier combination for primary therapy of essential hypertension? 

It must stay first line both on economy and scientific grounds – although the Drug Industry wishes  it suppressed as has occurred in UK and WHO – EU and RSA State Drug lists, without any scientific reasons given.

Reserpine is not  “a tragic victim of myths, marketing, and fashionable prescribing” as Myhr quotes Fraser 1999 below. The analogy is lithium for bipolar disease, and metformin for diabetes and the prediabetes syndromes (overweight, hypertension,  infertility), which  gold standard old drugs were denied to the USA public  for twenty years  by the malignant control that Big Pharma wielded and still wields through it’s buying power  over the FDA and other Regulators. 

       The progressive suppression of reserpine by the EU and RSA can only be the result of disinformation spread by the New Prescription Designer Drug industry through it’s expert paid lobbyists in Academia, journals  and on Regulatory Committees. 

      Contrary to Fraser, there is no “fashionable prescribing” in socialist -controlled pharmacopoeas like the UK NHS, Europe or the state sector in South Africa- the (supra)national Authorities  have simply bowed to the financial might of manufacturers and banned  reserpine from their formularies, since governments (like the Disease Industry) earn far more from new designer drug registration and  tax revenues than from the old and proven like metformin, lithium and reserpine.

This is the essence  of Naomi Klein’s Disaster Capitalism (The Shock Doctrine 2007),  Al Gore’s The Assault on Reason (2007).

           But  for the same reason that even USA had to licence lithium and metformin – they are the best and proven therapies in their class-  lowdose reserpine must be reinstated as baseline therapy for hypertension in RSA and the EU.

3. Up to now on Medline,

          at least a dozen RCTs show that no single antihypertensive drug does better than lowdose (co-) thiazide. 

          at least a dozen RCTs show that solo lowdose reserpine is at least as good as if not better than any other single drug.

          at least 25 RCTs show that the combination of lowdose reserpine + lowdose co-thiazide/amiloride is unsurpassed

 

– so no drug company has dared to do any more head-on comparative trials .

 

             The latest of these trials – SHEP  and now ALLHAT – after the two definng German Reserpine Group  RCTs (Pittrow ea 1997)  –  show that even as third-line add-on ie in the most resistant cases, reserpine is unsurpassable.   

 

              The reserpine RCTs confirm that lowdose reserpine   corrects some of the metabolic adversity of higher-dose thiazide, without the adverse effects of the newer alpha/beta/ACE/ARB/CCB  blockers.  For safety and efficacy, amlodipine may be the nearest equal of reserpine – but it does not have all the  benefits of reserpine.. New studies confirm that lowdose reserpine is both major antidepressant-anxiolytic,  anti-parkinsonian, and a major anti-addiction herb extract.

 

4. and the Cache County study (2006)    showed that  “the use of potassium-sparing diuretics alone without any other antihypertensive medication was associated with a significant 90% reduction in Alzheimer’s Disease  risk   (aHR, 0.09; 95% CI, 0.01-0.41).

 

 

5. COSTING: Even in mid-2008, in South Africa a vigorous dose of co-amiloretic 13.5mg plus reserpine 0.1mg per day costs RETAIL as little as R15 or US2 a month – and many patients need only half those doses to control mild to moderate HBP. But if bulk bought by the RSA State for the millions of hypertensive state patients, the combination could cost as little as US$0.5 a year for actual ingredients. But in terms of disaster capitalism, such optimal therapy that  greatly improves healthspan and productivity suits  neither the pharmaceutical industry,  nor the State who depend on jobs, fees  and taxes  from a thriving pharmaceutical industry.  When we offered this option two year ago, the experts chose to ignore it…

 

6. IGNORING THE BROAD PATHOGENESIS OF AGING DISEASE: However, all the commercial ie prescription drugs discussed above hardly address the core pathogenesis of common essential HBP. 

The patented drugs deal with salt and water retention and  vasoconstriction, but  none work against obesity- metabolic syndrome, free radiclal lipoxidation inflammation, atheroma, and stress-related  hypercorticolism;  and only ACEI/ ARBs counter-act insulin resistance, tissue glycation ie reduce new diabetes.  

 

eg in the HOPE trial (2000) of ramipril vs placebo in ~66yr  old largely obese vascular-risk patients, the 5year death rate on placebo was 12.2% vs 10.4% on ramipril (-16%, p0.005)-  but if anything there were more noncardiovascular deaths on ramipril (4.3%) than on placebo(4.1%). New cases of diabetes were 1/3 lower on ramipril than on placebo (5.4%).

but  in the Univ Texas metaanalysis of ACEI and ARB trials (2006), these drugs reduced the incidence of new diabetes by only 20%.  

 

But  with marketed antihypertensive drugs, no reduction in the non-vascular scourges of the aging –  fractures, obesity, cancer or dementia –  was reported:

    neither the HYVET-COG trial  (2008) in those over 80yrs, nor the 2006 Cochrane metanalysis showed any benefit in lowering dementia with antihypertensives in hypertensive patients.

     In a 4year study from New Zealand Reid 2007  showed no significant improvement in hip or spine bone density from 50mg HCThiazide a day;    but a 2006 Canadian metanalysis   showed that thiazides  or betablocker or ACEI for hypertension reduced the incidence of any fracture by a significant 14 to 19%.

 

ADDRESSING THE PATHOGENESIS OF PREMATURE AGING DEGENERATIVE DISEASE: The insignificant results of focussing just on antihypertensives- no reduction in obesity, non-stroke dementia, cancer, and small reduction in fractures and dementia-

contrast with the result of 

*appropriate HRT in menopausal women in the WHI and Oulu 10year trials: about onethird reduction in all major events-  fractures, new diabetes, cardiovascular, cancer and dementing problems – and thus in all-cause mortality;

*and metformin in the three major diabetes prevention programs- about 50% reduction in new diabetes;

*and metformin in the UKPDS and Canadian 5 to 20year studies-   reduction of mortality by a third to half;

*and natural supplements for the depleting and polluted  food chain and environment – fish oil plus a simple appropriate blend of the 13 vitamins, +-13 essential minerals, and the ~25 invaluable other antioxidant nitric-oxide booster  biologicals which lower insulin resistance – lipidemia,   hypertension, obesity, free radical  lipoxidation and thus arteriosclerosis; and  all the  other major chronic degenerative diseases of aging: eg CoQ10, arginine, carnitine, ribose, proline,  N-acetylcysteine, malic acid, GABA, 5HTP, taurine, chondroglucosamine,  MSMethane, curcumin, galega, gymnema, coleus, sawpalm etc.

 

ndb

 

E d i t o r i a l  THE JOURNAL OF CLINICAL HYPERTENSION  2007: 9 591-4
Getting to Goal Blood Pressure:   Why Reserpine Deserves a Second Look
Joshua Barzilay,  Kaiser Permanente ea,

 This multiauthor editorial  reviewed several  hypertension trials in which reserpine therapy was used with good results,

and presented  new data from the Multiple Risk Factor Intervention Trial (MRFIT) that also demonstrate  the positive effects of reserpine.They believe that reserpine deserves reconsideration as an effective  antihypertensive medication, especially in combination therapy.


“By 2004, the prevalence of hypertension increased in USA  to 29% mainly as a result of increased  obesity and population age, while blood pressure (BP) control rates improved  to 37%.     Despite this recent success, BP control rates  remain low.  

Reasons for this include  lack of careful follow-up; failure to control systolic BP,  especially in older patients; and therapeutic inertia (ie, failure to increase the dose of medication  or add  another medication when BP is not at goal).

Until recently, even in the best clinical trials,  BP control rates of only 66% to 73% have been achieved even  with a 2-drug combination as initial therapy,

 

“One antihypertensive medication that could be used to improve BP control, especially systolic BP, is reserpine, a centrally acting adrenergic antagonist. It  fell into disfavor years ago, labeled  a relic from the past and an obsolete medication. While its use in westernized countries fell precipitously in the past decades despite its proven efficacy, reserpine is still used extensively  in nonwesternized countries, where health care expenditures are more costconstrained.
In South Africa, for example, it is a second-step hypertension medication after diuretic therapy. In India, low-dose reserpine, in combination with diuretics and hydralazine, is used effectively to prevent renal disease.

Several adverse effects –  depression, gastric bleeding, and breast cancer- attributed to reserpine  in the 1950s and 1960s led to its near demise. . Early in its use, recommended dosages of reserpine  varied from 0.75 mg to 10 mg/d;  but studies using   low dosages  0.05–0.1 mg/d usually in combination  with diuretics) show that reserpine is well tolerated

At current dosing levels, no increase in depression,  dyspepsia or breast cancer have been reported.

 

“The situation of reserpine is analogous in many ways to that of thiazide diuretic therapy. Early in their use, high dosages of diuretics (often up to 200 mg/d) were prescribed, and  associated with  high rates of adverse biochemical effects and little additional antihypertensive efficacy..

“Today, low-dose thiazide diuretics (ie, 12.5–50 mg/d) are the recommended first-step agents in the treatment of hypertension.

Early hypertension outcome studies, such as the Veterans Administration (VA) Cooperative Studies in the 1960s, the Hypertension Detection and Follow-Up Program (HDFP) in the 1970s, and MRFIT in the 1980s, established that low-dose reserpine therapy was an effective treatment for most hypertensives.

 

Table. Change in BP With the Addition of Step 2 Medication in MRFITa
                                                        SBP                                 DBP
STEP 2 MEDICATION     N         MEAN         SE                     MEAN              SE
Reserpine                         445        –7.8            0.6                     –6.5                 0.4
Methyldopa or propanolol 370      –4.1            1.1                     –3.8                 0.7

 

“Further analysis of the MRFIT dataset, presented here for the first time (Table), indicates that  reserpine add-on therapy in men treated with diuretic monotherapy through the first year of the  study was more successful in lowering systolic and diastolic BP than  propranolol or methyldopa..


“Several VA cooperative studies in the 1980s also demonstrated the efficacy of reserpine: In the Hypertension in the Elderly VA study, men aged 60 years or older, approximately 40% did not respond to thiazide monotherapy, and second-step medications were added. Results showed equal efficacy of methyldopa,
hydralazine, metoprolol, and reserpine and equal duration of action. Measures of cognitive behavioral effects, such as depression, diminished cognitive abilities, and changes in activities of daily living, did not differ between the groups; however, reported adverse effects and withdrawal due to drug intolerance were higher with methyldopa.

 

“With reserpine there were no reported adverse effects that were increased, but with reserpine  postural dizziness and headache were reduced, and serum cholesterol levels decreased  the most  (–16 mg/dL).

 

“The most recent clinical hypertension trial  reporting on the use of reserpine was the Systolic Hypertension in the Elderly Program (SHEP)  in more than 4700 adults aged 60+ years;  it  was the first to demonstrate the efficacy of low-dose antihypertensive medication in preventing stroke (by 35%) and cardiovascular events (by 32%) in people with isolated systolic hypertension (defined as systolic BP >160 mm Hg and diastolic BP <90 mm Hg). The active treatment group (n=2365) received a low dosage of chlorthalidone (12.5–25.0 mg/d) with a step up to atenolol (25.0–50.0 mg/d) or reserpine (0.05–0.10 mg/d), if needed. During the 4.5 years of average follow-up,  8% (n=193) received  reserpine over a mean exposure period of 1.7 years .For reserpine, the relative risk (vs nonuse of reserpine) and 95% confidence intervals were 0.65 (0.26–1.59) for mortality, 0.27 (0.04–2.26) for stroke, 0.93(0.29–2.96) for coronary heart disease events, and 0.55 (0.20–1.49) for cardiovascular disease events. 

All these  values are considerably lower than those associated with atenolol use (0.84;  1.34 ;1.04 and 1.07, respectively),  a medication still in wide use. These  results are similar to those of MRFIT.

Given the new results  from MRFIT and the results of the VA Cooperative trial and SHEP, it would appear that reserpine still has a role in the management of hypertension. The question arises: how should it be used?

 

“It is now commonly accepted practice to initiate antihypertensive therapy with 2
antihypertensive medications in persons with stage 2 hypertension.


“The most common combination  is a diuretic with either an angiotensin converting  enzyme (ACE)  inhibitor/angiotensin II receptor blocker (ARB) or a calcium channel blocker  (CCB).

 In many cases, especially in older persons and those with diabetes and obesity,

2 medications are not completely effective and ≥3 medications  may be required, as experienced in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial  (ALLHAT).  

 Persons with diabetes usually are obese. When obesity is centrally distributed, insulin resistance is present, and with it the metabolic syndrome. It has been estimated that among US adults aged 60 years or older, ≈65% have hypertension and ≈40% have the metabolic syndrome.

 One consequence of insulin resistance is increased sympathetic tone and thus elevated BP.

In these obese individuals,  blockade of increased sympathetic tone  with reserpine, through reduction of  peripheral and central noradrenaline stores, may have a salutary effect in BP control.

 

“Combining a diuretic, which decreases the excess fluid volume associated with the metabolic  syndrome,  and an ACE inhibitor/ARB or CCB,  which protects endothelial function and/or decreases vascular resistance,  represents an effective  treatment plan for the clinician in BP management.

This is in keeping with  growing awareness that combination therapy is an effective means of treatment  but more may have to be done in some patients. The use of reserpine, an additional option, may provide for improvement in management in these individuals. Reserpine is an effective BP-lowering agent. It
is most effective in the elderly and the obese, often when systolic BP is the limiting goal BP measure. It has a very long duration of action (days) and may therefore be helpful in partially adherent patients.

 

“At present, there are no pharmaceutical advocates for the use of reserpine or a clinical trial to test its effects on clinical outcomes. It will only be at the behest of the medical community that consideration be given for the use of low-dosage reserpine (0.05–0.10 mg once daily, often at bedtime) to better control BP. While the exact place for its use can be debated, we believe it deserves strong consideration.”

 

MEMORANDUM  From: Kirsten Myhr, MscPharm, MPH, Member Expert Advisory Panel on Drug Policies and Management http://archives.who.int/eml/expcom/expcom12/kmyhrmemo.docDate: 6 April 2002  To: Co-ordinator, WHO EDL Committee meeting April 2002

Subject: Revision of the essential drugs list

Reserpine

“I think there is documentation to support keeping it as a low cost alternative. Here are five relevant references from Medline, note in particular that it is included in the guidelines in South Africa, even after a recent revision of the guidelines.

1. Kronig B, Pittrow DB, Welzel D, Weidinger G. Different concepts in first-line treatment of essential hypertension. Comparison of  low-dose reserpine-thiazide combination with nitrendipine monotherapy. German Reserpine in Hypertension Study Group. Hypertension. 1997;29: 651-8.     

 2. Griebenow R, Pittrow DB, Weidinger G, Mueller E, Mutschler E, Welzel D.Low-dose reserpine/thiazide combination in first-line treatment of hypertension: efficacy and safety compared to an ACE inhibitor. Blood Press. 1997; 6(5): 299-306.

3. Manyemba J. A randomised crossover comparison of reserpine and sustained-release nifedipine in hypertension. Cent Afr J Med. 1997 Dec;43(12): 344-9.

4. Seedat YK. Hypertension in developing nations in sub-Saharan Africa. J Hum Hypertens. 2000 Oct-Nov;14(10-11): 739-47. Review.

5. Hypertension clinical guideline 2000. S Afr Med J. 2001 Feb; 91(2 Pt 2):163-72.

6. Fraser HS. Reserpine: a tragic victim of myths, marketing, and fashionable prescribing.
Clin Pharmacol Ther. 1996 Oct; 60(4): 368-73.

Advertisements

One response to “Getting to Goal Blood Pressure despite Disaster Capitalism: Why Reserpine Deserves a Second Look

  1. Pingback: Healthspanlife – the Official Life! Blog

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s