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.
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
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
“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.